Substituted benzimidazole dosage forms and method of using same

ABSTRACT

There is provided a solid pharmaceutical composition in a dosage form that is not enteric-coated, having active ingredients including a non-enteric coated proton pump inhibitor and at least one buffering agent. The proton pump inhibitor is omeprazole, lansoprazole, rabeprazole, esomeprazole, pantoprazole, pariprazole, and leminoprazole, or an enantiomer, isomer, derivative, free base, or salt thereof, in an amount of approximately 5 mg to approximately 300 mg; and the buffering agent is in an amount of approximately 0.1 mEq to approximately 2.5 mEq per mg of proton pump inhibitor. The dosage form includes a suspension tablet, a chewable tablet, an effervescent powder, or an effervescent tablet. Also provided is a method for treating an acid-related gastrointestinal disorder in a subject in need thereof by administering to the subject a solid pharmaceutical composition.

This application is a continuation-in-part of U.S. patent applicationSer. No. 09/183,422 filed on Oct. 30, 1998, now abandoned, which is acontinuation-in-part of U.S. patent application Ser. No. 08/680,376filed on Jul. 15, 1996, now U.S. Pat. No. 5,840,737, which claimspriority to U.S. Provisional Application Serial No. 60/009,608 filed onJan. 4, 1996. This application claims priority to all such previousapplications, and such applications are hereby incorporated herein byreference.

TECHNICAL FIELD

The present invention relates to pharmaceutical preparations comprisingsubstituted benzimidazole proton pump inhibitors.

BACKGROUND OF THE INVENTION

Omeprazole is a substituted benzimidazole,5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole,that inhibits gastric acid secretion. Omeprazole belongs to a class ofantisecretory compounds called proton pump inhibitors (“PPIs”) that donot exhibit anti-cholinergic or H₂ histamine antagonist properties.Drugs of this class suppress gastric acid secretion by the specificinhibition of the H⁺, K⁺-ATPase enzyme system (proton pump) at thesecretory surface of the gastric parietal cell.

Typically, omeprazole, lansoprazole and other proton pump inhibitors areformulated in an enteric-coated solid dosage form (as either adelayed-release capsule or tablet) or as an intravenous solution (or asa product for reconstitution), and are prescribed for short-termtreatment of active duodenal ulcers, gastric ulcers, gastroesophagealreflux disease (GERD), severe erosive esophagitis, poorly responsivesystematic GERD, and pathological hypersecretory conditions such asZollinger Ellison syndrome. These conditions are caused by an imbalancebetween acid and pepsin production, called aggressive factors, andmucous, bicarbonate, and prostaglandin production, called defensivefactors. These above-listed conditions commonly arise in healthy orcritically ill patients, and may be accompanied by significant uppergastrointestinal bleeding.

H₂-antagonists, antacids, and sucralfate are commonly administered tominimize the pain and the complications related to these conditions.These drugs have certain disadvantages associated with their use. Someof these drugs are not completely effective in the treatment of theaforementioned conditions and/or produce adverse side effects, such asmental confusion, constipation, diarrhea, and thrombocytopenia.H₂-antagonists, such as ranitidine and cimetidine, are relatively costlymodes of therapy, particularly in NPO patients, which frequently requirethe use of automated infusion pumps for continuous intravenous infusionof the drug.

Patients with significant physiologic stress are at risk forstress-related gastric mucosal damage and subsequent uppergastrointestinal bleeding (Marrone and Silen, Pathogenesis, Diagnosisand Treatment of Acute Gastric Mucosa Lesions, Clin Gastroenterol 13:635-650 (1984)). Risk factors that have been clearly associated with thedevelopment of stress-related mucosal damage are mechanical ventilation,coagulopathy, extensive burns, head injury, and organ transplant (Zinneret al., The Prevention of Gastrointestinal Tract Bleeding in Patients inan Intensive Care Unit, Surg. Gynecol. Obstet., 153: 214-220 (1981);Larson et al., Gastric Response to Severe Head Injury, Am. J. Surg. 147:97-105 (1984); Czaja et al., Acute Gastroduodenal Disease After ThermalInjury: An Endoscopic Evaluation of Incidence and Natural History, NEngl. J. Med, 291: 925-929 (1974); Skillman et al., Respiratory Failure,Hypotension, Sepsis and Jaundice: A Clinical Syndrome Associated withLethal Hemorrhage From Acute Stress Ulceration, Am. J. Surg., 117:523-530 (1969); and Cook et al., Risk Factors for GastrointestinalBleeding in Critically Ill Patients, N. Engl. J. Med., 330:377-381(1994)). One or more of these factors are often found in critically ill,intensive care unit patients. A recent cohort study challenges otherrisk factors previously identified such as acid-base disorders, multipletrauma, significant hypertension, major surgery, multiple operativeprocedures, acute renal failure, sepsis, and coma (Cook et al., RiskFactors for Gastrointestinal Bleeding in Critically Ill Patients, N.Engl. J. Med., 330:377-381 (1994)). Regardless of the risk type,stress-related mucosal damage results in significant morbidity andmortality. Clinically significant bleeding occurs in at least twentypercent of patients with one or more risk factors who are left untreated(Martin et al., Continuous Intravenous cimetidine DecreasesStress-related Upper Gastrointestinal Hemorrhage Without PromotingPneumonia, Crit. Care Med., 21: 19-39 ('1993)). Of those who bleed,approximately ten percent require surgery (usually gastrectomy) with areported mortality of thirty percent to fifty percent (Czaja et al.,Acute Gastroduodenal Disease After Thermal Injury: An EndoscopicEvaluation of Incidence and Natural History, N Engl. J. Med, 291:925-929 (1974); Peura and Johnson, Cimetidine for Prevention andTreatment of Gastroduodenal Mucosal Lesions in Patients in an IntensiveCare Unit, Ann Intern Med., 103: 173-177 (1985)). Those who do not needsurgery often require multiple transfusions and prolongedhospitalization. Prevention of stress-related upper gastrointestinalbleeding is an important clinical goal.

In addition to general supportive care, the use of drugs to preventstress-related mucosal damage and related complications is considered bymany to be the standard of care (AMA Drug Evaluations). However, generalconsensus is lacking about which drugs to use in this setting (Martin etal., Continuous Intravenous Cimetidine Decreases Stress-related UpperGastrointestinal Hemorrhage Without Promoting Pneumonia, Crit. CareMed., 21: 19-39 (1993); Gafter et al., Thrombocytopenia Associated WithHypersensitivity to Ranitidine: Possible Cross-reactivity withCimetidine, Am. J. Gastroenterol, 64: 560-562 (1989) Martin et al.,Stress Ulcers and Organ Failure in Intubated Patients in SurgicalIntensive Care Units, Ann Surg., 215: 332-337 (1992)). In two recentmeta-analyses (Cook et al., Stress Ulcer Prophylaxis in the CriticallyIll: A Meta-analysis, Am. J. Med., 91: 519-527 (1991); Tryba, StressUlcer Prophylaxis—Quo Vadis? Intens. Care Med. 20: 311-313 (1994))Antacids, sucralfate, and H₂-antagonists were all found to be superiorto placebo and similar to one another in preventing uppergastrointestinal bleeding. Yet, prophylactic agents are withdrawn infifteen to twenty percent of patients in which they are employed becauseof failure to prevent bleeding or control pH (Ostro et al., Control ofGastric pH With Cimetidire Boluses Versus Primed Infusions,Gastroenterology, 89: 532-537 (1985) Siepler, A Dosage Alternative forH-2 Receptor Antagonists, Continuous-Infusion, Clin. Ther., 8 (Suppl A):24-33 (1986); Ballesteros et al., Bolus or Intravenous Infusion ofRanitidine: Effects on Gastric pH and Acid Secretion: A Comparison ofRelative Cost and Efficacy, Ann. Intern. Med., 112:334-339 (1990)), orbecause of adverse effects (Gafter et al., Thrombocytopenia AssociatedWith Hypersensitivity to Ranitidine: Possible Cross-reactivity WithCimetidine, Am. J. Gastroenterol, 64: 560-562 (1989); Sax, ClinicallyImportant Adverse Effects and Drug Interactions With H2-ReceptorAntagonists: An Update, Pharmacotherapy 7(6 pt 2): 110S-115S (1987);Vial et al., Side Effects of Ranitidine, Drug Saf, 6:94-117(1991); Cantuand Korek, Central Nervous System Reactions to Histamine-2 ReceptorBlockers, Ann. Intern Med., 114: 1027-1034 (1991); and Spychal andWickham, Thrombocytopenia Associated With Ranitidine, Br. Med. J., 291:1687 (1985)). In addition, the characteristics of an ideal agent for theprophylaxis of stress gastritis were analyzed by Smythe and Zarowitz,Changing Perspectives of Stress Gastritis Prophylaxis, Ann Pharmacother,28: 1073-1084 (1994) who concluded that none of the agents-currently inuse fulfill their criteria.

Stress ulcer prophylaxis has become routine therapy in intensive careunits in most hospitals (Fabian et al., Pneumonia and Stress Ulcerationin Severely Injured Patients, Arch. Surg., 128: 185-191 (1993); Cook etal., Stress Ulcer Prophylaxis in the Critically Ill: A Meta-Analysis,Am. J. Med., 91: 519-527 (1991)). Controversy remains regardingpharmacologic intervention to prevent stress-related bleeding incritical care patients. It has been suggested that the incidence andrisk of gastrointestinal bleeding has decreased in the last ten yearsand drug therapy may no longer be needed (Cook et al., Risk Factors forGastrointestinal Bleeding in Critically Ill. Patients, N. Engl. J. Med.,330:377-381 (1994); Tryba, Stress Ulcer Prophylaxis—Quo Vadis? Intens.Care Med. 20: 311-313 (1994); Schepp, Stress Ulcer Prophylaxis.: Still aValid Option in the 1990s?, Digestion 54: 189-199 (1993)). Thisreasoning is not supported by a recent placebo-controlled study. Martin.et al. conducted a prospective, randomized, double-blind,placebo-controlled comparison of continuous-infusion cimetidine andplacebo for the prophylaxis of stress-related mucosal damage. The studywas terminated early because of excessive bleeding-related mortality inthe placebo group. It appears that the natural course of stress-relatedmucosal damage in a patient at risk who receives no prophylaxis remainssignificant. In the placebo group, thirty-three percent (33%) ofpatients developed clinically significant bleeding, nine percent (9%)required transfusion, and six percent (6%) died due to bleeding-relatedcomplications. In comparison, fourteen percent (14%) ofcimetidine-treated patients developed clinically significant bleeding,six percent (6%) required transfusions, and one and one-half percent(1.5%) died due to bleeding-related complication. The difference inbleeding rates between treatment groups was statistically significant.This study clearly demonstrated that continuous-infusion cimetidinereduced morbidity in critical care patients. Although these data wereused to support the approval of continuous-infusion cimetidine by theFood and Drug Administration for stress ulcer prophylaxis,H₂-antagonists fall short of being the optimal pharmacotherapeuticagents for preventing of stress-related mucosal bleeding.

Another controversy surrounding stress ulcer prophylaxis is which drugto use. In addition to the various H₂-antagonists, antacids andsucralfate are other treatment options for the prophylaxis ofstress-related mucosal damage. An ideal drug in this setting shouldpossess the following characteristics: prevent stress ulcers and theircomplications, be devoid of toxicity, lack drug interactions, beselective, have minimal associated costs (such as personnel time andmaterials), and be easy to administer (Smythe and Zarowitz, ChangingPerspectives of Stress Gastritis Prophylaxis, Ann Pharmacother, 28:1073-1084 (1994)). Some have suggested that sucralfate is possibly theideal agent for stress ulcer prophylaxis (Smythe and Zarowitz, ChangingPerspectives of Stress Gastritis Prophylaxis, Ann Pharmacother, 28:1073-1084 (1994)). Randomized, controlled studies support the use ofsucralfate (Borrero et al., Antacids vs. Sucralfate in Preventing AcuteGastrointestinal Tract Bleeding in Abdominal Aortic Aurgery, Arch.Surg., 121: 810-812 (1986); Tryba, Risk of Acute Stress Bleeding andNosocomial Pneumonia in Ventilated Intensive Care Patients. Sucralfatevs. Antacids, Am. J. Med., 87(3B): 117-124 (1987); Cioffi et al.,Comparison of Acid Neutralizing and Non-acid Neutralizing Stress UlcerProphylaxis in Thermally Injured Patients. J. Trauma, 36: 541-547(1994); and Driks et al., Nosocomial Pneumonia in Intubated PatientsGiven Sucralfate as Compared With Antacids or Histamine Type 2 Blockers,N. Engl. J. Med., 317: 1376-1382 1987)), but data on critical carepatients with head injury, trauma, or burns are limited. In addition, arecent study comparing sucralfate and cimetidine plus antacids forstress ulcer prophylaxis reported clinically significant bleeding inthree of forty-eight (6%) sucralfate-treated patients, one of whomrequired a gastrectomy (Cioffi et al., Comparison of Acid Neutralizingand Non-acid Neutralizing Stress Ulcer Prophylaxis in Thermally InjuredPatients, J. Trauma, 36: 541-547 (1994)). In the study performed byDriks and coworkers that compared sucralfate to conventional therapy(H₂-antagonists, antacids, or H₂-antagonists plus antacids), the onlypatient whose death was attributed to stress-related uppergastrointestinal bleeding was in the sucralfate arm (Driks et al.,Nosocomial Pneumonia in Intubated Patients Given Sucralfate as ComparedWith Antacids or Histamine Type 2 Blockers, N. Engl. J. Med., 317:1376-1382(1987)).

H₂-antagonists fulfill many of the criteria for an ideal stress ulcerprophylaxis drug. Yet, clinically significant bleeds can occur during.H₂-antagonist prophylaxis (Martin et al., Continuous IntravenousCimetidine Decreases Stress-related Upper Gastrointestinal HemorrhageWithout Promoting Pneumonia, Crit. Care Med., 21: 19-39 (1993); Cook etal. , Stress Ulcer Prophylaxis in the Critically Ill: A Meta-analysis,Am. J. Med., 91: 519-527 (1991); Schuman et al., Prophylactic Therapyfor Acute Ulcer Bleeding: A Reappraisal, Ann Intern. Med, 106: 562-567(1987)). Adverse events are not uncommon in the critical care population(Gafter et al., Thrombocytopenia Associated With Hypersensitivity toRanitidine: Possible Cross-Reactivity With Cimetidine, Am. J.Gastroenterol, 64: 560-562 (1989); Sax, Clinically Important AdverseEffects and Drug Interactions With H2-receptor Antagonists: An Update,Pharmacotherapy 7(6 pt 2): 110S-115S (1987); Vial et al., Side Effectsof Ranitidine, Drug Saf., 6:94-117(1991); Cantu and Korek, CentralNervous System Reactions to Histamine-2 Receptor Blockers, Ann. InternMed., 114: 1027-1034 (1991); Spychal and Wickham, ThrombocytopeniaAssociated With Ranitidine, Br. Med. J., 291: 1687 (1985)).

One reason proposed for the therapeutic H₂-antagonist failures is lackof pH control throughout the treatment period (Ostro et al., Control ofGastric pH With Cimetidine Boluses Versus Primed Infusions,Gastroenterology, 89: 532-537 (1985)). Although the precisepathophysiologic mechanisms involved in stress ulceration are notclearly established, the high concentration of hydrogen ions in themucosa (Fiddian-Green et al., 1987) or gastric fluid in contact withmucosal cells appears to be an important factor. A gastric pH >3.5 hasbeen associated with a lower incidence of stress-related mucosal damageand bleeding (Larson et al., Gastric Response to Severe Head Injury, Am.J. Surg. 147: 97-105 (1984); Skillman et al., Respiratory Failure,Hypotension, Sepsis and Jaundice: A Clinical Syndrome Associated WithLethal Hemorrhage From Acute Stress Ulceration, Am. J. Surg., 117:523-530 (1969); Skillman et al., The Gastric Mucosal Barrier: Clinicaland Experimental Studies in Critically Ill and Normal Man and in theRabbit, Ann Surg., 172: 564-584 (1970); and Priebe and Skillman, Methodsof Prophylaxis in Stress Ulcer Disease, World J. Surg., 5: 223-233(1981)). Several studies have shown that H₂-antagonists, even in maximaldoses, do not reliably or continuously increase intragastric pH abovecommonly targeted levels (3.5 to 4.5). This is true especially when usedin fixed-dose bolus regimens (Ostro et al., Control of Gastric pH WithCimetidine Boluses Versus Primed Infusions, Gastroenterology, 89:532-537 (1985); Siepler, A Dosage Alternative for H-2 ReceptorAntagonists, Continuous-infusion, Clin. Ther. , 8 (Suppl A): 24-33(1986); Ballesteros et al., Bolus or Intravenous Infusion of Ranitidine:Effects on Gastric pH and Acid Secretion: A Comparison of Relative Costand Efficacy, Ann. Intern. Med., 112:334-339 (1990)). In addition,gastric pH levels tend to trend downward with time when using acontinuous-infusion of H₂-antagonists, which may be the result oftachyphylaxis (Ostro et al., Control of Gastric pH With CimetidineBoluses Versus Primed Infusions, Gastroenterology, 89: 532-537 (1985);Wilder-Smith and Merki, Tolerance During Dosing With H₂-receptorAntagonists. An Overview, Scand. J. Gastroenterol 27 (suppl. 193): 14-19(1992)).

Because stress ulcer prophylaxis is frequently employed in the intensivecare unit, it is essential from both a clinical and economic standpointto optimize the pharmacotherapeutic approach. In an attempt to identifyoptimal therapy, cost of care becomes an issue. All treatment costsshould be considered, including the costs of treatment failures anddrug-related adverse events. While the actual number of failuresresulting in mortality is low, morbidity (e.g., bleeding that requiresblood transfusion) can be high, even though its association with thefailure of a specific drug is often unrecognized.

Initial reports of increased frequency of pneumonia in patientsreceiving stress ulcer prophylaxis with agents that raise gastric pH hasinfluenced the pharmacotherapeutic approach to management of criticalcare patients. However, several recent studies (Simms et al., Role ofGastric Colonization in the Development of Pneumonia in Critically IllTrauma Patients: Results of a Prospective Randomized Trial, J. Trauma,31: 531-536 (1991); Pickworth et al., Occurrence of Nasocomial Pneumoniain Mechanically Ventilated Trauma Patients: A Comparison of Sucralfateand Ranitidine, Crit. Care Med., 12: 1856-1862 (1993); Ryan et al.,Nasocomial Pneumonia During Stress Ulcer Prophylaxis With Cimetidine andSucralfate, Arch. Surg., 128: 1353-1357 (1993); Fabian et al., Pneumoniaand Stress Ulceration in Severely Injured Patients, Arch. Surg., 128:185-191 (1993)), a meta-analysis (Cook et al., Stress Ulcer Prophylaxisin the Critically Ill: A Meta-analysis, Am. J. Med., 91: 519-527(1991)), and a closer examination of the studies that initiated theelevated pH-associated pneumonia hypotheses (Schepp, Stress UlcerProphylaxis: Still a Valid Option in the 1990s?, Digestion 54: 189-199(1993)) cast doubt on a causal relationship. The relationship betweenpneumonia and antacid therapy is much stronger than for H₂-antagonists.The shared effect of antacids and H₂-antagonists on gastric pH seems anirresistible common cause explanation for nosocomial pneumonia observedduring stress ulcer prophylaxis. However, there are importantdifferences between these agents that are not often emphasized (Laggneret al., Prevention of Upper Gastrointestinal Bleeding in Long-termVentilated Patients, Am. J. Med., 86 (suppl 6A) : 81-84 (1989)). Whenantacids are exclusively used to control pH in the prophylaxis ofstress-related upper gastrointestinal bleeding, large volumes areneeded. Volume, with or without subsequent reflux, may be the underlyingmechanism(s) promoting the development of pneumonia in susceptiblepatient populations rather than the increased gastric pH. The rate ofpneumonia (12%) was not unexpected in this critical care population andcompares with sucralfate, which does not significantly raise gastric pH(Pickworth et al., Occurrence of Nasocomial Pneumonia in MechanicallyVentilated Trauma Patients: A Comparison of Sucralfate and Ranitidine,Crit. Care Med., 12: 1856-1862 (1993); Ryan et al., Nasocomial PneumoniaDuring Stress Ulcer Prophylaxis With Cimetidine and Sucralfate, Arch.Surg., 128: 1353-1357 (1993)).

Omeprazole (Prilosec®), lansoprazole (Prevacid®) and other PPIs reducegastric acid production by inhibiting H⁺,K⁺-ATPase of the parietalcell-the final common pathway for gastric acid secretion (Fellenius etal., Substituted Benzimidazoles Inhibit Gastric Acid Secretion byBlocking H⁺,K⁺-ATPase, Nature, 290: 159-161 (1981); Wallmark et al, TheRelationship Between Gastric Acid Secretion and Gastric H⁺,K⁺-ATPaseActivity, J. Biol. Chem., 260: 13681-13684 (1985); Fryklund et al.,Function and Structure of Parietal Cells After H⁺,K⁺-ATPase Blockade,Am. J. Physiol., 254 (3 pt 1) ; G399-407 (1988)).

PPIs contain a sulfinyl group in a bridge between substitutedbenzimidazole and pyridine rings, as illustrated below.

At neutral pH, omeprazole, lansoprazole and other PPIs are chemicallystable, lipid-soluble, weak bases that are devoid of inhibitoryactivity. These neutral weak bases reach parietal cells from the bloodand diffuse into the secretory canaliculi, where the drugs becomeprotonated and thereby trapped. The protonated agent rearranges to forma sulfenic acid and a sulfenamide. The sulfenamide interacts covalentlywith sulfhydryl groups at critical sites in the extracellular (luminal)domain of the membrane-spanning H⁺,K⁺-ATPase (Hardman et al., Goodman &Gilman's The Pharmacological Basis of Therapeutics, p. 907 (9^(th) ed.1996)). Omeprazole and lansoprazole, therefore, are prodrugs that mustbe activated to be effective. The specificity of the effects of PPIs isalso dependent upon: (a) the selective distribution of H⁺,K⁺-ATPase; (b)the requirement for acidic conditions to catalyze generation of thereactive inhibitor; and (c) the trapping of the protonated drug and thecationic sulfenamide within the acidic canaliculi and adjacent to thetarget enzyme. (Hardman et al., 1996)).

Omeprazole and lansoprazole are available for oral administration asenteric coated particles in gelatin capsules. Other proton pumpinhibitors such as rabeprazole and pantoprazole are supplied as entericcoated tablets. The enteric dosage forms of the prior art have beenemployed because it is very important that these drugs not be exposed togastric acid prior to absorption. Although these drugs are stable atalkaline pH, they are destroyed rapidly as pH falls (e.g., by gastricacid). Therefore, if the microencapsulation or the enteric coating isdisrupted (e.g., trituration to compound a liquid, or chewing thecapsule), the drug will be exposed to degradation by the gastric acid inthe stomach.

The absence of an intravenous or oral liquid dosage form in theUnited-States has limited the testing and use of omeprazole,lansoprazole and rabeprazole in the critical care patient population.Barie et al., Therapeutic Use of Omeprazole for RefractoryStress-induced Gastric Mucosal Hemorrhage, Crit. Care Med., 20: 899-901(1992) have described the use of omeprazole enteric-coated pelletsadministered through a nasogastric tube to control gastrointestinalhemorrhage in a critical care patient with multi-organ failure. However,such pellets are not ideal as they can aggregate and occlude such tubes,and they are not suitable for patients who cannot swallow the pellets.Am J. Health-Syst Pharm 56:2327-30 (1999).

Proton pump inhibitors such as omeprazole represent an advantageousalternative to the use of H₂-antagonists, antacids, and sucralfate as atreatment for complications related to stress-related mucosal damage.However, in their current form (capsules containing enteric-coatedgranules or enteric-coated tablets), proton pump inhibitors can bedifficult or impossible to administer to patients who areeither-unwilling or unable to swallow tablets or capsules, such ascritically ill patients, children, the elderly, and patients sufferingfrom dysphagia. Therefore, it would be desirable to formulate a protonpump inhibitor solution or suspension which can be enterally deliveredto a patient thereby providing the benefits of the proton pump inhibitorwithout the drawbacks of the current enteric-coated solid dosage forms.

Omeprazole, the first proton pump inhibitor introduced into use, hasbeen formulated in many different embodiments such as in a mixture ofpolyethylene glycols, adeps solidus and sodium lauryl sulfate in asoluble, basic amino acid to yield a formulation designed foradministration in the rectum as taught by U.S. Pat. No. 5,219,870 toKim.

U.S. Pat. No. 5,395,323 to Berglund ('323) discloses a device for mixinga pharmaceutical from a solid supply into a parenterally acceptableliquid form for parenteral administration to a patient. The '323 patentteaches the use of an omeprazole tablet which is placed in the deviceand dissolved by normal saline, and infused parenterally into thepatient. This device and method of parenteral infusion of omeprazoledoes not provide the omeprazole solution as an enteral product, nor isthis omeprazole solution directly administered to the diseased oraffected areas, namely the stomach and upper gastrointestinal tract, nordoes this omeprazole formulation provide the immediate antacid effect ofthe present formulation..

U.S. Pat. No. 4,786,505 to Lovgren et al. discloses a pharmaceuticalpreparation containing omeprazole together with an alkaline reactingcompound or an alkaline salt of omeprazole optionally together with analkaline compound as a core material in a tablet formulation. The use ofthe alkaline material, which can be chosen from such substances as thesodium salt of carbonic acid, are used to form a “micro-pH” around eachomeprazole particle to protect the omeprazole which is highly sensitiveto acid pH. The powder mixture is then formulated to small beads,pellets, tablets and may be loaded into capsules by conventionalpharmaceutical procedures. This formulation of omeprazole does notprovide an omeprazole dosage form which can be enterally administered toa patient who may be unable and/or unwilling to swallow capsules,tablets or pellets, nor does it teach a convenient form which can beused to make an omeprazole or other proton pump inhibitor solution orsuspension.

Several buffered omeprazole oral solutions/suspensions have beendisclosed. For example, Pilbrant et al., Development of an OralFormulation of Omeprazole, Scand. J. Gastroent. 20 (Suppl. 108): 113-120(1985) teaches the use of micronized omeprazole suspended in water,methylcellulose and sodium bicarbonate in a concentration ofapproximately 1.2 mg omeprazole/ml suspension.

Andersson et el., Pharmacokinetics of Various Single Intravenous andOral Doses of Omeprazole, Eur J. Clin. Pharmacol. 39:, 195-197 (1990)discloses 10 mg, 40 mg, and 90 mg of oral omeprazole dissolved in PEG400, sodium bicarbonate and water. The concentration of omeprazolecannot be determined as volumes of diluent are not disclosed.Nevertheless, it is apparent from this reference that multiple doses ofsodium bicarbonate were administered with and after the omeprazolesuspension.

Andersson et al., Pharmacokinetics and Bioavailability of OmeprazoleAfter Single and Repeated Oral Administration in Healthy Subjects, Br.J. Clin. Pharmac. 29: 557-63 (1990) teaches the oral use of 20 mg ofomeprazole, which was dissolved in 20 g of PEG 400 (sp. gravity=1.14)and diluted with 50 ml of sodium bicarbonate, resulting in aconcentration of 0.3 mg/ml.

Regardh et al., The Pharmacokinetics of Omeprazole in Humans—A Study ofSingle Intravenous and Oral Doses, Ther. Drug Mon. 12: 163-72 (1990)discloses an oral dose of omeprazole at a concentration 0.4 mg/ml afterthe drug was dissolved in PEG 400, water and sodium bicarbonate.

Landahl et al., Pharmacokinetics Study of Omeprazole in Elderly HealthyVolunteers, Clin. Pharmacokinetics 23 (6): 469-476 (1992) teaches theuse of an oral dose of 40 mg of omeprazole dissolved in PEG 400, sodiumbicarbonate and water. This reference does not disclose the finalconcentrations utilized. Again, this reference teaches the multipleadministration of sodium bicarbonate after the omeprazole solution.

Andersson et al., Pharmacokinetics of [¹⁴C] Omeprazole in Patients withLiver Cirrhosis, Clin. Pharmacokinetics 24(1): 71-78 (1993) disclosesthe oral administration of 40 mg of omeprazole which was dissolved inPEG 400, water and sodium bicarbonate. This reference does not teach thefinal concentration of the omeprazole solution administered, although itemphasizes the need for concomitant sodium bicarbonate dosing to preventacid degradation of the drug.

Nakagawa, et al., Lansoprazole: Phase I Study of lansoprazole (AG-1749)Anti-ulcer Agent, J. Clin. Therapeutics & Med. (1991) teaches the oraladministration of 30 mg of lansoprazole suspended in 100 ml of sodiumbicarbonate (0.3 mg/ml), which was administered to patients through anasogastric tube.

All of the buffered omeprazole solutions described in these referenceswere administered orally, and were given to healthy subjects who wereable to ingest the oral dose. In all of these studies, omeprazole wassuspended in a solution including sodium bicarbonate, as a pH buffer, inorder to protect the acid sensitive omeprazole during administration. Inall of these studies, repeated administration of sodium bicarbonate bothprior to, during, and following omeprazole administration were requiredin order to prevent acid degradation of the omeprazole given via theoral route of administration. In the above-cited studies, as much as 48mmoles of sodium bicarbonate in 300 ml of water must be ingested for asingle dose of omeprazole to be orally administered.

The buffered omeprazole solutions of the above cited prior art requirethe ingestion of large amounts of sodium bicarbonate and large volumesof water by repeated administration. This has been considered necessaryto prevent acid degradation of the omeprazole. In the above-citedstudies, basically healthy volunteers, rather than sick patients, weregiven dilute buffered omeprazole utilizing pre-dosing and post-dosingwith large volumes of sodium bicarbonate.

The administration of large amounts of sodium bicarbonate can produce atleast six significant adverse effects, which can dramatically reduce theefficacy of the omeprazole in patients and reduce the overall health ofthe patients. First, the fluid volumes of these dosing protocols wouldnot be suitable for sick or critically ill patients who must receivemultiple doses of omeprazole. The large volumes would result in thedistention of the stomach and increase the likelihood of complicationsin critically ill patients such as the aspiration of gastric contents.

Second, because bicarbonate is usually neutralized in the stomach or isabsorbed, such that belching results, patients with gastroesophagealreflux may exacerbate or worsen their reflux disease as the belching cancause upward movement of stomach acid (Brunton, Agents for the Controlof Gastric Acidity and Treatment of Peptic Ulcers, In, Goodman A G, etal. The Pharmacologic Basis of Therapeutics (New York, p. 907 (1990)).

Third, patients with conditions such as hypertension or heart failureare standardly advised to avoid the intake of excessive sodium as it cancause aggravation or exacerbation of their hypertensive conditions(Brunton, supra). The ingestion of large amounts of sodium bicarbonateis inconsistent with this advice.

Fourth, patients with numerous conditions that typically accompanycritical illness should avoid the intake of excessive sodium bicarbonateas it can cause metabolic alkalosis that can result in a seriousworsening of the patient's condition.

Fifth, excessive antacid intake (such as sodium bicarbonate) can resultin drug interactions that produce serious adverse effects. For example,by altering gastric and urinary pH, antacids can alter rates of drugdissolution and absorption, bioavailability, and renal elimination(Brunton, supra).

Sixth, because the buffered omeprazole solutions of the prior artrequire prolonged administration of sodium bicarbonate, it makes itdifficult for patients to comply with the regimens of the prior art. Forexample, Pilbrant. et al. disclose an oral omeprazole administrationprotocol calling for the administration to a subject who has beenfasting for at least ten hours, a solution of 8 mmoles of sodiumbicarbonate in 50 ml of water. Five minutes later, the subject ingests asuspension of 60 mg of omeprazole in 50 ml of water that also contains 8mmoles of sodium bicarbonate. This is rinsed down with another 50 ml of8 mmoles sodium bicarbonate solution. Ten minutes after the ingestion ofthe omeprazole dose, the subject ingests 50 ml of bicarbonate solution(8 mmoles). This is repeated at twenty minutes and thirty minutes postomeprazole dosing to yield a total of 48 mmoles of, sodium bicarbonateand 300 ml of water in total which are ingested by the subject for asingle omeprazole dose. Not only does this regimen require the ingestionof excessive amounts of bicarbonate and water, which is likely to bedangerous to some patients, it is unlikely that even healthy patientswould comply with this regimen.

It is well documented that patients who are required to follow complexschedules for drug administration are non-compliant and, thus, theefficacy of the buffered omeprazole solutions of the prior art would beexpected to be reduced due to non-compliance. Compliance has been foundto be markedly reduced when patients are required to deviate from aschedule of one or two (usually morning and night) doses of a medicationper day. The use of the prior art buffered omeprazole solutions whichrequire administration protocols with numerous steps, different drugs(sodium bicarbonate+omeprazole+PEG 400 versus sodium bicarbonate alone),and specific time allotments between each stage of the total omeprazoleregimen in order to achieve efficacious results is clearly in contrastwith both current drug compliance theories and human nature.

The prior art (Pilbrant et al., 1985) teaches that the bufferedomeprazole suspension can be stored at refrigerator temperatures for aweek and deep frozen for a year while still maintaining 99% of itsinitial potency. It would be desirable to have an omeprazole or otherproton pump inhibitor solution or suspension that could be stored atroom temperature or in a refrigerator, for periods of time which exceedthose of the prior art while still maintaining 99% of the initialpotency. Additionally, it would be advantageous to have a form of theomeprazole and bicarbonate which can be utilized to instantly make theomeprazole solution/suspension of the present invention which issupplied in a solid form which imparts the advantages of improvedshelf-life at room temperature, lower cost to produce, less expensiveshipping costs, and which is less expensive to store.

It would, therefore, be desirable to have a proton pump inhibitorformulation, which provides a cost-effective means for the treatment ofthe aforementioned conditions without the adverse effect profile of H₂receptor antagonists, antacids, and sucralfate. Further, it would bedesirable to have a proton pump inhibitor formulation which isconvenient to prepare and administer to patients unable to ingest soliddosage forms such as tablets or capsules, which is rapidly absorbed, andcan be orally or enterally delivered as a liquid form or solid form. Itis desirable that the liquid formulation not clog indwelling tubes, suchas nasogastric tubes or other similar tubes, and which acts as anantacid immediately upon delivery.

It would further be advantageous to have a potentiator or enhancer ofthe pharmacological activity of the PPIs. It has been theorized byapplicant that the PPIs can only exert their effects on H⁺,K⁺-ATPasewhen the parietal cells are active. Accordingly, applicant hasidentified, as discussed below, parietal cell activators that areadministered to synergistically enhance the activity of the PPIs.

Additionally, the intravenous dosage forms of PPIs of the prior art areoften administered in larger doses than the oral forms. For example, thetypical adult IV dose of omeprazole is greater than 100 mg/day whereasthe adult oral dose is 20 to 40 mg/day. Large IV doses are necessary toachieve the desired pharmacologic effect because, it is believed, manyof the parietal cells are in a resting phase (mostly inactive) during anIV dose given to patients who are not taking oral substances by mouth(npo) and, therefore, there is little active (that which is insertedinto the secretory canalicular membrane) H⁺,K⁺-ATPase to inhibit.Because of the clear disparity in the amount of drug necessary for IVversus oral doses, it would be very advantageous to have compositionsand methods for IV administration where significantly less drug isrequired.

SUMMARY OF THE INVENTION AND ADVANTAGES

The foregoing advantages and objects are accomplished by the presentinvention. The present invention provides an oral solution/suspensioncomprising a proton pump inhibitor and at least one buffering agent. ThePPI can be any substituted benzimidazole compound having H⁺,K⁺-ATPaseinhibiting activity and being unstable to acid. Omeprazole andlansoprazole are the preferred PPIs for use in oral suspensions inconcentrations of at least 1.2 mg/ml and 0.3 mg/ml, respectively. Theliquid oral compositions can be further comprised of parietal cellactivators, anti-foaming agents and/or flavoring agents.

The inventive composition can alternatively be formulated as a powder,tablet, suspension tablet, chewable tablet, capsule, effervescentpowder, effervescent tablet, pellets and granules. Such dosage forms areadvantageously devoid of any enteric coating or delayed orsustained-release delivery mechanisms, and comprise a PPI and at leastone buffering agent to protect the PPI against acid degradation. Similarto the liquid dosage form, the dry forms can further includeanti-foaming agents, parietal cell activators and flavoring agents.

Kits utilizing the inventive dry dosage forms are also disclosed hereinto provide for the easy preparation of a liquid composition from the dryforms.

In accordance with the present invention, there is further provided amethod of treating gastric acid disorders by administering to a patienta pharmaceutical composition comprising a proton pump inhibitor in apharmaceutically acceptable carrier and at least one buffering agentwherein the administering step comprises providing a patient with asingle dose of the composition without requiring further administeringof the buffering agent.

Additionally, the present invention relates to a method for enhancingthe pharmacological activity of an intravenously administered protonpump inhibitor in which at least one parietal cell activator is orallyadministered to the patient before, during and/or after the intravenousadministrations of the proton pump inhibitor.

BRIEF DESCRIPTION OF THE DRAWINGS

Other advantages of the present invention will be readily appreciated asthe same becomes better understood by reference to the followingdetailed description when considered in connection with the accompanyingdrawing wherein:

FIG. 1 is a graph showing the effect of the omeprazole solution of thepresent invention on gastric pH in patients at risk for uppergastrointestinal bleeding from stress-related mucosal damage;

FIG. 2 is a flow chart illustrating a patient enrollment scheme;

FIG. 3 is a bar graph illustrating gastric pH both pre- andpost-administration of omeprazole solution according to the presentinvention; and

FIG. 4 is a graph illustrating the stomach pH values after the oraladministration of both chocolate plus lansoprazole and lansoprazolealone.

DETAILED DESCRIPTION OF THE INVENTION

In general, the present invention relates to a pharmaceuticalcomposition comprising a proton pump inhibitor and a buffering agentwith or without one or more parietal cell activators. While the presentinvention may be embodied in many different forms, several specificembodiments are discussed herein with the understanding that the presentdisclosure is to be considered only as an exemplification of theprinciples of the invention, and it is not intended to limit theinvention to the embodiments illustrated.

For the purposes of this application, the term “proton pump inhibitor”(PPI) shall mean any substituted benzimidazole possessingpharmacological activity as an inhibitor of H⁺,K⁺-ATPase, including, butnot limited to, omeprazole, lansoprazole, pantoprazole, rabeprazole,dontoprazole, perprazole (s-omeprazole magnesium), habeprazole,ransoprazole, pariprazole, and leminoprazole in neutral form or a saltform, a single enantiomer or isomer or other derivative or an alkalinesalt of an enantiomer of the same.

The inventive composition comprises dry formulations, solutions and/orsuspensions of the proton pump inhibitors. As used herein, the terms“suspension” and “solution” are interchangeable with each other and meansolutions and/or suspensions of the substituted benzimidazoles.

After absorption of the PPI (or administration intravenously) the drugis delivered via the bloodstream to various tissues and cells of thebody including the parietal cells. Research suggests that the PPI is inthe form of a weak base and is non-ionized and thereby freely passesthrough physiologic membranes, including the cellular membranes of theparietal cell. It is believed that the non-ionized PPI moves into theacid-secreting portion of the parietal cell, the secretory canaliculus.Once in the acidic millieu of the secretory canaliculus, the PPI isapparently protonated (ionized) and converted to the active form of thedrug. Generally, ionized proton pump inhibitors are membrane impermeableand form disulfide covalent bonds with cysteine residues in the alphasubunit of the proton pump.

The inventive pharmaceutical composition comprising a proton pumpinhibitor such as omeprazole, lansoprazole or other proton pumpinhibitor and derivatives thereof can be used for the treatment orprevention of gastrointestinal conditions including, but not limited to,active duodenal ulcers, gastric ulcers, gastroesophageal reflux disease(GERD), severe erosive esophagitis, poorly responsive systematic GERD,and pathological hypersecretory conditions such as Zollinger EllisonSyndrome. Treatment of these conditions is accomplished by administeringto a patient an effective amount of the pharmaceutical compositionaccording to the present invention.

The proton pump inhibitor is administered and dosed in accordance withgood medical practice, taking into account the clinical condition of theindividual patient, the site and method of administration, scheduling ofadministration, and other factors known to medical practitioners. Theterm “effective amount” means, consistent with considerations known inthe art, the amount of PPI or other agent effective to achieve apharmacologic effect or therapeutic improvement without undue adverseside effects, including but not limited to, raising of gastric pH,reduced gastrointestinal bleeding, reduction in the need for bloodtransfusion, improved survival rate, more rapid recovery, parietal cellactivation and H⁺,K⁺-ATPase inhibition or improvement or elimination ofsymptoms, and other indicators as are selected as appropriate measuresby those skilled in the art.

The dosage range of omeprazole or other proton pump inhibitors such assubstituted benzimidazoles and derivatives thereof can range fromapproximately <2 mg/day to approximately 300 mg/day. The standardapproximate daily oral dosage is typically 20 mg of omeprazole, 30 mglansoprazole, 40 mg pantoprazole, 20 mg rabeprazole, and thepharmacologically equivalent doses of the following PPIs: habeprazole,pariprazole, dontoprazole, ransoprazole, perprazole (s-omeprazolemagnesium), and leminoprazole.

A pharmaceutical formulation of the proton pump inhibitors utilized inthe present invention can be administered orally or enterally to thepatient. This can be accomplished, for example, by administering thesolution via a nasogastric (ng) tube or other indwelling tubes placed inthe GI tract. In order to avoid the critical disadvantages associatedwith administering large amounts of sodium bicarbonate, the PPI solutionof the present invention is administered in a single dose which does notrequire any further administration of bicarbonate, or large amounts ofbicarbonate, or other buffer following the administration of the PPIsolution, nor does it require a large amount of bicarbonate or buffer intotal. That is, unlike the prior art PPI solutions and administrationprotocols outlined above, the formulation of the present invention isgiven in a single dose which does not require administration ofbicarbonate either before or after administration of the PPI. Thepresent invention eliminates the need to pre-or post-dose withadditional volumes of water and sodium bicarbonate. The amount ofbicarbonate administered via the single dose administration of thepresent invention is less than the amount of bicarbonate administered astaught in the prior art references cited above.

Preparation of Oral Liquids

The liquid oral pharmaceutical composition of the present invention isprepared by mixing omeprazole (Prilosec® AstraZeneca) or other protonpump inhibitor or derivatives thereof with a solution including at leastone buffering agent (with or without a parietal cell activator, asdiscussed below). Preferably, omeprazole or other proton pump inhibitor,which can be obtained from a capsule or tablet or obtained from thesolution for parenteral administration, is mixed with a sodiumbicarbonate solution to achieve a desired final omeprazole (or otherPPI) concentration. As an example, the concentration of omeprazole inthe solution can range from approximately 0.4 mg/ml to approximately10.0 mg/ml. The preferred concentration for the omeprazole in thesolution ranges from approximately 1.0 mg/ml to approximately 4.0 mg/ml,with 2.0 mg/ml being the standard concentration. For lansoprazole(Prevacid® TAP Pharmaceuticals, Inc.) the concentration can range fromabout 0.3 mg/ml to 10 mg/ml with the preferred concentration being about3 mg/ml.

Although sodium bicarbonate is the preferred buffering agent employed inthe present invention to protect the PPI against acid degradation, manyother weak and strong bases (and mixtures thereof) can be utilized. Forthe purposes of this application, “buffering agent” shall mean anypharmaceutically appropriate weak base or strong base (and mixturesthereof) that, when formulated or delivered with (e.g., before, duringand/or after) the PPI, functions to substantially prevent or inhibit theacid degradation of the PPI by gastric acid sufficient to preserve thebioavailability of the PPI administered. The buffering agent isadministered in an amount sufficient to substantially achieve the abovefunctionality. Therefore, the buffering agent of the present invention,when in the presence of gastric acid, must only elevate the pH of thestomach sufficiently to achieve adequate bioavailability of the drug toeffect therapeutic action.

Accordingly, examples of buffering agents include, but are not limitedto, sodium bicarbonate, potassium bicarbonate, magnesium hydroxide,magnesium lactate, magnesium glucomate, aluminum hydroxide, aluminumhydroxide/sodium bicarbonate coprecipitate, a mixture of an amino acidand a buffer, a mixture of aluminum glycinate and a buffer, a mixture ofan acid salt of an amino acid and a buffer, and a mixture of an alkalisalt of an amino acid and a buffer. Additional buffering agents includesodium citrate, sodium tartarate, sodium acetate, sodium carbonate,sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate,potassium pyrophosphate, disodium hydrogenphosphate, dipotassiumhydrogenphosphate, trisodium phosphate, tripotassium phosphate, sodiumacetate, potassium metaphosphate, magnesium oxide, magnesium hydroxide,magnesium carbonate, magnesium silicate, calcium acetate, calciumglycerophosphate, calcium cholride, calcium hydroxide, calcium lactate,calcium carbonate, calcium bicarbonate, and other calcium salts.

The pharmaceutically acceptable carrier of the oral liquid preferablycomprises a bicarbonate salt of Group IA metal as buffering agent, andcan be prepared by mixing the bicarbonate salt of the Group IA metal,preferably sodium bicarbonate, with water. The concentration of thebicarbonate salt of the Group IA metal in the composition generallyranges from approximately 5.0 percent to approximately 60.0 percent.Preferably, the concentration of the bicarbonate salt of the Group IAmetal ranges from approximately 7.5 percent to approximately 10.0percent. In a preferred embodiment of the present invention, sodiumbicarbonate is the preferred salt and is present in a concentration ofapproximately 8.4 percent.

More specifically, the amount of sodium bicarbonate 8.4% used in thesolution of the present invention is approximately 1 mEq (or mmole)sodium bicarbonate per 2 mg omeprazole, with a range of approximately0.2 mEq (mmole) to 5 mEq (mmole) per 2 mg of omeprazole.

In a preferred embodiment of the present invention, enterically-coatedomeprazole particles are obtained from delayed release capsules(Prilosec® AstraZeneca). Alternatively, omeprazole powder can be used.The enterically coated omeprazole particles are mixed with a sodiumbicarbonate (NaHCO₃) solution (8.4%), which dissolves the entericcoating and forms an omeprazole solution. The omeprazole solution haspharmacokinetic advantages over standard time-released omeprazolecapsules, including: (a) more rapid drug absorbance time (about 10 to 60minutes) following administration for the omeprazole solution versusabout 1 to 3 hours following administration for the enteric-coatedpellets; (b) the NaHCO₃ solution protects the omeprazole from aciddegradation prior to absorption; (c) the NaHCO₃ acts as an antacid whilethe omeprazole is being absorbed; and (d) the solution can beadministered through an existing indwelling tube without clogging, forexample, nasogastric or other feeding tubes (jejunal or duodenal),including small bore needle catheter feeding tubes.

Additionally, various additives can be incorporated into the inventivesolution to enhance its stability, sterility and isotonicity. Further,antimicrobial preservatives, antioxidants, chelating agents, andadditional buffers can be added, such as ambicin. However,microbiological evidence shows that this formulation inherentlypossesses antimicrobial and antifungal activity. Various antibacterialand antifungal agents such as, for example, parabens, chlorobutanol,phenol, sorbic acid, and the like can enhance prevention of the actionof microorganisms.

In many cases, it would be desirable to include isotonic agents, forexample, sugars, sodium chloride, and the like. Additionally, thickeningagents such as methylcellulose are desirable to use in order to reducethe settling of the omeprazole or other PPI or derivatives thereof fromthe suspension.

The liquid oral solution may further comprise flavoring agents (e.g.,chocolate, root beer or watermelon) or other flavorings stable at pH 7to 9, anti-foaming agents (e.g., simethicone 80 mg, Mylicon®) andparietal cell activators (discussed below).

The present invention further includes a pharmaceutical compositioncomprising omeprazole or other proton pump inhibitor and derivativesthereof and at least one buffering agent in a form convenient forstorage, whereby when the composition is placed into an aqueoussolution, the composition dissolves yielding a suspension suitable forenteral administration to a subject. The pharmaceutical composition isin a solid form prior to dissolution or suspension in an aqueoussolution. The omeprazole or other PPIs and buffering agent can be formedinto a tablet, capsule, pellets or granules, by methods well known tothose skilled in the art.

The resultant omeprazole solution is stable at room temperature forseveral weeks and inhibits the growth of bacteria or fungi as shown inExample X below. Indeed, as established in Example XIII, the solutionmaintains greater than 90% of its potency for 12 months. By providing apharmaceutical composition including omeprazole or other PPI with bufferin a solid form, which can be later dissolved or suspended in aprescribed amount of aqueous solution to yield the desired concentrationof omeprazole and buffer, the cost of production, shipping, and storageare greatly reduced as no liquids are shipped (reducing weight andcost), and there is no need to refrigerate the solid form of thecomposition or the solution. Once mixed the resultant solution can thenbe used to provide dosages for a single patient over a course of time,or for several patients.

Tablets and Other Solid Dosage Forms

As mentioned above, the formulations of the present invention can alsobe manufactured in concentrated forms, such as tablets, suspensiontablets and effervescent tablets or powders, such that upon reactionwith water or other diluent, the aqueous form of the present inventionis produced for oral, enteral or parenteral administration.

The present pharmaceutical tablets or other solid dosage formsdisintegrate rapidly in aqueous media and form an aqueous solution ofthe PPI and buffering agent with minimal shaking or agitation. Suchtablets utilize commonly available materials and achieve these and otherdesirable objectives. The tablets or other solid dosage forms of thisinvention provide for precise dosing of a PPI that may be of lowsolubility in water. They are particularly useful for medicatingchildren and the elderly and others in a way that is much moreacceptable than swallowing or chewing a tablet. The tablets that areproduced have low friability, making them easily transportable.

The term “suspension tablets” as used herein refers to compressedtablets which rapidly disintegrate after they are placed in water, andare readily dispersible to form a suspension containing a precise dosageof the PPI. The suspension tablets of this invention comprise, incombination, a therapeutic amount of a PPI, a buffering agent, and adisintegrant. More particularly, the suspension tablets comprise about20 mg omeprazole and about 1-20 mEq of sodium bicarbonate.

Croscarmellose sodium is a known disintegrant for tablet formulations,and is available from FMC Corporation, Philadelphia, Pa. under thetrademark Ac-Di-Sol®. It is frequently blended in compressed tabletingformulations either alone or in combination with microcrystallinecellulose to achieve rapid disintegration of the tablet.

Microcrystalline cellulose, alone or coprocessed with other ingredients,is also a common additive for compressed tablets and is well known forits ability to improve compressibility of difficult to compress tabletmaterials. It is commercially available under the Avicel® trademark. Twodifferent Avicel® products are utilized, Avicel® PH which ismicrocrystalline cellulose, and Avicel® AC-815, a coprocessed spraydried residue of microcrystalline cellulose and a calcium, sodiumalginate complex in which the calcium to sodium ratio is in the range ofabout 0.40:1 to about 2.5:1. While AC-815 is comprised of 85%microcrystalline cellulose (MCC) and 15% of a calcium, sodium alginatecomplex, for purposes of the present invention this ratio may be variedfrom about 75% MCC to 25% alginate up to about 95% MCC to 5% alginate.Depending on the particular formulation and active ingredient, these twocomponents may be present in approximately equal amounts or in unequalamounts, and either may comprise from about 10% to about 50% by weightof the tablet.

The suspension tablet composition may, in addition to the ingredientsdescribed above, contain other ingredients often used in pharmaceuticaltablets, including flavoring agents, sweetening agents, flow aids,lubricants or other common tablet adjuvants, as will be apparent tothose skilled in the art. Other disintegrants, such as crospbvidone andsodium starch glycolate may be employed, although croscarmellose sodiumis preferred.

In addition to the suspension tablet, the solid formulation of thepresent invention can be in the form of a powder, a tablet, a capsule,or other suitable solid dosage form (e.g., a pelleted form or aneffervescing tablet, troche or powder), which creates the inventivesolution in the presence of diluent or upon ingestion. For example, thewater in the stomach secretions or water which is used to swallow thesolid dosage form can serve as the aqueous diluent.

Compressed tablets are solid dosage forms prepared by compacting aformulation containing an active ingredient and excipients selected toaid the processing and improve the properties of the product. The term“compressed tablet” generally refers to a plain, uncoated tablet fororal ingestion, prepared by a single compression or by pre-compactiontapping followed by a final compression.

Such solid forms can be manufactured as is well known in the art. Tabletforms can include, for example, one or more of lactose, mannitol, cornstarch, potato starch, microcrystalline cellulose, acacia, gelatin,colloidal silicon dioxide, croscarmellose sodium, talc, magnesiumstearate, stearic acid, and other excipients, colorants, diluents,buffering agents, moistening agents, preservatives, flavoring agents,and pharmaceutically compatible carriers. The manufacturing processesmay employ one, or a combination of, four established methods: (1) drymixing; (2) direct compression; (3) milling; and (4) non-aqueousgranulation. Lachman et al., The Theory and Practice of IndustrialPharmacy (1986). Such tablets may also comprise film coatings, whichpreferably dissolve upon oral ingestion or upon contact with diluent.

Non-limiting examples of buffering agents which could be utilized insuch tablets include sodium bicarbonate, alkali earth metal salts suchas calcium carbonate, calcium hydroxide, calcium lactate, calciumglycerophosphate, calcium acetate, magnesium carbonate, magnesiumhydroxide, magnesium silicate, magnesium aluminate, aluminum hydroxideor aluminum magnesium hydroxide. A particular alkali earth metal saltuseful for making an antacid tablet is calcium carbonate.

An example of a low density alkali earth metal salt useful for makingthe granules according to the present invention is extra light calciumcarbonate available from Specialty Minerals Inc., Adams, Me. The densityof the extra light calcium carbonate, prior to being processed accordingto the present invention, is about 0.37 gm/ml.

The granules used to make the tablets according to one embodiment of thepresent invention are made by either spray drying or pre-compacting theraw materials. Prior to being processed into granules by either process,the density of the alkali earth metal salts useful in the presentinvention ranges from about 0.3 gm/ml to about 0.55 gm/ml, preferablyabout 0.35 gm/ml to about 0.45 gm/ml, even more preferably about 0.37gm/ml to about 0.42 gm/ml.

Additionally, the present invention can be manufactured by utilizingmicronized compounds in place of the granules or powder. Micronizationis the process by which solid drug particles are reduced in size. Sincethe dissolution rate is directly proportional to the surface area of thesolid, and reducing the particle size increases the surface area,reducing the particle size increases the dissolution rate. Althoughmicronization results in increased surface area possibly causingparticle aggregation, which can negate the benefit of micronization andis an expensive manufacturing step, it does have the significant benefitof increasing the dissolution rate of relatively water insoluble drugs,such as omeprazole and other proton pump inhibitors.

The present invention also relates to administration kits to ease mixingand administration. A month's supply of powder or tablets, for example,can be packaged with a separate month's supply of diluent, and are-usable plastic dosing cup. More specifically, the package couldcontain thirty (30) suspension tablets containing 20 mg omeprazole each,1 L sodium bicarbonate 8.4% solution, and a 30 ml dose cup. The userplaces the tablet in the empty dose cup, fills it to the 30 ml mark withthe sodium bicarbonate, waits for it to dissolve (gentle stirring oragitation may be used), and then ingests the suspension. One skilled inthe art will appreciate that such kits may contain many differentvariations of the above components. For example, if the tablets orpowder are compounded to contain PPI and buffering agent, the diluentmay be water, sodium bicarbonate, or other compatible diluent, and thedose cup can be larger than 30 ml in size. Also, such kits can bepackaged in unit dose form, or as weekly, monthly, or yearly kits, etc.

Although the tablets of this invention are primarily intended as asuspension dosage form, the granulations used to form the tablet mayalso be used to form rapidly disintegrating chewable tablets, lozenges,troches, or swallowable tablets. Therefore, the intermediateformulations as well as the process for preparing them provideadditional novel aspects of the present invention.

Effervescent tablets and powders are also prepared in accordance withthe present invention. Effervescent salts have been used to dispersemedicines in water for oral administration. Effervescent salts aregranules or coarse powders containing a medicinal agent in a drymixture, usually composed of sodium bicarbonate, citric acid andtartaric acid. When the salts are added to water, the acids and the basereact to liberate carbon dioxide gas, thereby causing “effervescence.”

The choice of ingredients for effervescent granules. depends both uponthe requirements of the manufacturing process and the necessity ofmaking a preparation which dissolves readily in water. The two requiredingredients are at least one acid and at least one base. The basereleases carbon dioxide upon reaction with the acid. Examples of suchacids include, but are not limited to, tartaric acid and citric acid.Preferably, the acid is a combination of both tartaric acid and citricacid. Examples of bases include, but are not limited to, sodiumcarbonate, potassium bicarbonate and sodium bicarbonate. Preferably, thebase is sodium bicarbonate, and the effervescent combination has a pH ofabout 6.0 or higher.

Effervescent salts preferably include the following ingredients, whichactually produce the effervescence: sodium bicarbonate, citric acid andtartaric acid. When added to water the acids and base react to liberatecarbon dioxide, resulting in effervescence. It should be noted that anyacid-base combination which results in the liberation of carbon dioxidecould be used in place of the combination of sodium bicarbonate andcitric and tartaric acids, as long as the ingredients were suitable forpharmaceutical use, and result in a pH of about 6.0 or higher.

It should be noted that it requires 3 molecules of NaHCO3 (sodiumbicarbonate) to neutralize 1 molecule of citric acid and 2 molecules ofNaHCO3 to neutralize 1 molecule of tartaric acid. It is desired that theapproximate ratio of ingredients is as follows Citric Acid:TartaricAcid:Sodium Bicarbonate=1:2:3.44 (by weight). This ratio can be variedand continue to produce an effective release of carbon dioxide. Forexample, ratios of about 1:0:3 or 0:1:2 are also effective.

The method of preparation of the effervescent granules of the presentinvention employs three basic processes: wet and dry granulation, andfusion. The fusion method is used for the preparation of most commercialeffervescent powders. It should be noted that although these methods areintended for the preparation of granules, the formulations ofeffervescent salts of the present invention could also be prepared astablets, according to well known prior art technology for tabletpreparation.

Wet granulation is the oldest method of granule preparation. Theindividual steps in the wet granulation process of tablet preparationinclude milling and sieving of the ingredients; dry powder mixing; wetmassing; granulation; and final grinding.

Dry granulation involves compressing a powder mixture into a roughtablet or “slug” on a heavy-duty rotary tablet press. The slugs are thenbroken up into granular particles by a grinding operation, usually bypassage through an oscillation granulator. The individual steps includemixing of the powders; compressing (slugging); and grinding (slugreduction or granulation). No wet binder or moisture is involved in anyof the steps.

The fusion method is the most preferred method for preparing thegranules of the present invention. In this method, the compressing(slugging) step of the dry granulation process is eliminated. Instead,the powders are heated in an oven or other suitable source of heat.

PPIs Administered with Parietal Cell Activators

Applicant has unexpectedly discovered that certain compounds, such aschocolate, calcium and sodium bicarbonate and other alkaline substances,stimulate the parietal cells and enhance the pharmacologic activity ofthe PPI administered. For the purposes of this application, “parietalcell activator” shall mean any compound or mixture of compoundspossessing such stimulatory effect including, but not limited to,chocolate, sodium bicarbonate, calcium (e.g., calcium carbonate, calciumgluconate, calcium hydroxide, calcium acetate and calciumglycerophosphate), peppermint oil, spearmint oil, coffee, tea and colas(even if decaffeinated), caffeine, theophylline, theobromine, and aminoacids (particularly aromatic amino acids such as phenylalanine andtryptophan) and combinations thereof and the salts thereof.

Such parietal cell activators are administered in an amount sufficientto produce the desired stimulatory effect without causing untoward sideeffects to patients. For example, chocolate, as raw cocoa, isadministered in an amount of about 5 mg to 2.5 g per 20 mg dose ofomeprazole (or equivalent pharmacologic dose of other PPI). The dose ofactivator administered to a mammal, particularly a human, in the contextof the present invention should be sufficient to effect a therapeuticresponse (i.e., enhanced effect of PPI) over a reasonable time frame.The dose will be determined by the strength of the particularcompositions employed and the condition of the person, as well as thebody weight of the person to be treated. The size of the dose also willbe determined by the existence, nature, and extent of any adverse sideeffects that might accompany the administration of a particularcomposition.

The approximate effective ranges for various parietal cell activatorsper 20 mg dose of omeprazole (or equivalent dose of other PPI) are:

Chocolate (raw cocoa)—5 mg to 2.5 g

Sodium bicarbonate—7 mEq to 25 mEq

Calcium carbonate—1 mg to 1.5 Gm

Calcium gluconate—1 mg to 1.5 Gm

Calcium lactate—1 mg to 1.5 Gm

Calcium hydroxide—1 mg to 1.5 Gm

Calcium acetate—0.5 mg to 1.5 Gm

Calcium glycerophosphate—0.5 mg to 1.5 Gm

Peppermint oil—(powdered form) 1 mg to 1 Gm

Spearmint oil—(powdered form) 1 mg to 1 Gm

Coffee—20 ml to 240 ml

Tea—20 ml to 240 ml

Cola—20 ml to 240 ml

Caffeine—0.5 mg to 1.5 GM

Theophylline—0.5 mg to 1.5 GM

Theobromine—0.5 mg to 1.5 GM

Phenylalanine—0.5 mg to 1.5 GM

Tryptophan—0.5 mg to 1.5 GM

Pharmaceutically acceptable carriers are well-known to those who areskilled in the art. The choice of carrier will be determined, in part,both by the particular composition and by the particular method used toadminister the composition. Accordingly, there is a wide variety ofsuitable formulations of the pharmaceutical compositions of the presentinvention.

EXAMPLE I

A. Fast Disintegrating Suspension Tablets of Omeprazole

A fast disintegrating tablet is compounded as follows: Croscarmellosesodium 300 g is added to the vortex of a rapidly stirred beakercontaining 3.0 kg of deionized water. This slurry is mixed for 10minutes. Omeprazole 90 g (powdered) is placed in the bowl of a Hobartmixer. After mixing, the slurry of croscarmellose sodium is added slowlyto the omeprazole in the mixer bowl, forming a granulation which is thenplaced in trays and dried at 70° C. for three hours. The dry granulationis then placed in a blender, and to it is added 1,500 g of Avicel®AC-815 (85% microcrystalline cellulose coprocessed with 15% of acalcium, sodium alginate complex) and 1,500 g of Avicel® PH-302(microcrystalline cellulose). After this mixture is thoroughly blended,35 g of magnesium stearate is added and mixed for 5 minutes. Theresulting mixture is compressed into tablets on a standard tablet press(Hata HS). These tablets have an average weight of about 1.5 g, andcontain about 20 mg omeprazole. These tablets have low friability andrapid disintegration time. This formulation may be dissolved in anaqueous solution containing a buffering agent for immediate oraladministration.

Alternatively, the suspension tablet may be swallowed whole with asolution of buffering agent. In both cases, the preferred solution issodium bicarbonate 8.4%. As a further alternative, sodium bicarbonatepowder (about 975 mg per 20 mg dose of omeprazole (or an equipotentamount of other PPI) is compounded directly into the tablet. Suchtablets are then dissolved in water or sodium bicarbonate 8.4%, orswallowed whole with an aqueous diluent.

B. 10 mg Tablet Formula

Omeprazole 10 mg (or lansoprazole or pantoprazole or other PPI in anequipotent amount) Calcium lactate 175 mg Calcium glycerophosphate 175mg Sodium bicarbonate 250 mg Aspartame calcium (phenylalanine) 0.5 mgColloidal silicon dioxide 12 mg Corn starch 15 mg Croscarmellose sodium12 mg Dextrose 10 mg Peppermint 3 mg Maltodextrin 3 mg Mannitol 3 mgPregelatinized starch 3 mg

C. 20 mg Tablet Formula

Omeprazole 20 mg (or lansoprazole or pantoprazole or other PPI in anequipotent amount) Calcium lactate 175 mg Calcium glycerophosphate 175mg Sodium bicarbonate 250 mg Aspartame calcium (phenylalanine) 0.5 mgColloidal silicon dioxide 12 mg Corn starch 15 mg Croscarmellose sodium12 mg Dextrose 10 mg Peppermint 3 mg Maltodextrin 3 mg Mannitol 3 mgPregelatinized starch 3 mg

D. Tablet for Rapid Dissolution

Omeprazole 20 mg (or lansoprazole or pantoprazole or other PPI in anequipotent amount) Calcium lactate 175 mg Calcium glycerophosphate 175mg Sodium bicarbonate 500 mg Calcium hydroxide 50 mg Croscarmellosesodium 12 mg

E. Powder for Reconstitution for Oral Use (or per ng tube).

Omeprazole 20 mg (or lansoprazole or pantoprazole or other PPI in anequipotent amount) Calcium lactate 175 mg Calcium glycerophosphate 175mg Sodium bicarbonate 500 mg Calcium hydroxide 50 mg Glycerine 200 g

F. 10 mg Tablet Formula.

Omeprazole 10 mg (or lansoprazole or pantoprazole or other PPI in anequipotent amount) Calcium lactate 175 mg Calcium glycerophosphate 175mg Sodium bicarbonate 250 mg Polyethylene glycol 20 mg Croscarmellosesodium 12 mg Peppermint 3 mg Magnesium silicate 1 mg Magnesium stearate1 mg

G. 10 mg Tablet Formula

Omeprazole 10 mg (or lansoprazole or pantoprazole or other PPI in anequipotent amount) Calcium lactate 200 mg Calcium glycerophosphate 200mg Sodium bicarbonate 400 mg Croscarmellose sodium 12 mg Pregelatinizedstarch 3 mg

EXAMPLE II

Standard Tablet of PPI and Buffering Agent

Ten (10) tablets were prepared using a standard tablet press, eachtablet comprising about 20 mg omeprazole and about 975 mg sodiumbicarbonate uniformly dispersed throughout the tablet. To test thedissolution rate of the tablets, each was added to 60 ml of water. Usingpreviously prepared liquid omeprazole/sodium bicarbonate solution as avisual comparator, it was observed that each tablet was completelydispersed in under three (3) minutes.

Another study using the tablets compounded according to this Exampleevaluated the bioactivity of the tablets in five (5) adult critical carepatients. Each subject was administered one tablet via ng with a smallamount of water, and the pH of ng aspirate was monitored using papermeasure. The pH for each patient was evaluated for 6 hours and remainedabove 4, thus demonstrating the therapeutic benefit of the tablets inthese patients.

Tablets were also prepared by boring out the center of sodiumbicarbonate USP 975 mg tablets with a knife. Most of the removed sodiumbicarbonate powder was then triturated with the contents of a 20 mgPrilosec® capsule and the resulting mixture was then packed into thehole in the tablet and sealed with glycerin.

EXAMPLE III

PPI Central Core Tablet

Tablets are prepared in a two-step process. First, about 20 mg ofomeprazole is formed into a tablet as is known in the art to be used asa central core. Second, about 975 mg sodium bicarbonate USP is used touniformly surround the central core to form an outer protective cover ofsodium bicarbonate. The central core and outer cover are both preparedusing standard binders and other excipients to create a finished,pharmaceutically acceptable tablet.

EXAMPLE IV

Effervescent Tablets and Granules

The granules of one 20 mg Prilosec® capsule were emptied into a mortarand triturated with a pestle to a fine powder. The omeprazole powder wasthen geometrically diluted with about 958 mg sodium bicarbonate USP,about 832 mg citric acid USP and about 312 mg potassium carbonate USP toform a homogeneous mixture of effervescent omeprazole powder. Thispowder was then added to about 60 ml of water whereupon the powderreacted with the water to create effervescence. A bubbling solutionresulted of omeprazole and principally the antacids sodium citrate andpotassium citrate. The solution was then administered orally to oneadult male subject and gastric pH was measured using pHydrion paper. Theresults were as follows:

Time Interval pH Measured Immediately prior to dose 2 1 hour post dose 72 hours post dose 6 4 hours post dose 6 6 hours post dose 5 8 hours postdose 4

One skilled in the art of pharmaceutical compounding will appreciatethat bulk powders can be manufactured using the above ratios ofingredients, and that the a powder can be pressed into tablets usingstandard binders and excipients. Such tablets are then mixed with waterto activate the effervescent agents and create the desired solution. Inaddition, lansoprazole 30 mg (or an equipotent dose of other PPI) can besubstituted for omeprazole.

The effervescent powder and tablets can alternatively be formulated byemploying the above mixture but adding an additional 200 mg of sodiumbicarbonate USP to create a resulting solution with a higher pH.Further, instead of the excess 200 mg of sodium bicarbonate, 100 mg ofcalcium glycerophosphate or 100 mg of calcium lactate can be employed.Combinations of the same can also added.

EXAMPLE V

Parietal Cell Activator “Choco-Base™” Formulations and Efficacy

Children are affected by gastroesophageal reflux disease (GERD) withatypical manifestations. Many of these atypical symptoms are difficultto control with traditional drugs such as H₂-antagonists, cisapride, orsucralfate. PPIs are more effective in controlling gastric pH and thesymptoms of GERD than other agents. However, PPIs are not available indosage forms that are easy to administer to young children. To addressthis problem, applicant employed omeprazole or lansoprazole in abuffered chocolate suspension (Choco-Base, in children withmanifestations of GERD.

Applicant performed a retrospective evaluation of children with GERDreferred to the University of Missouri-Columbia from 1995 to 1998 whoreceived treatment with the experimental omeprazole or lansoprazoleChoco-Base suspension formulated in accordance with Formulation 1 statedbelow. Data were included on all patients with follow up informationsufficient to draw conclusions about pre/post treatment (usually >6months). There were 25 patients who met the criteria for thisevaluation. Age range was several weeks to greater than 5 years. Mostpatients had a history of numerous unsuccessful attempts at amelioratingthe effects of GERD. Medication histories indicated many trials ofvarious drugs.

The primary investigator reviewed all charts for uniformity of datacollection. When insufficient data was available in the Universitycharts, attempts were made to review charts in the local primary carephysicians' offices for follow-up data. If information was stillunavailable to review, attempts were made to contact family forfollow-up. If data were still unavailable the patients were consideredinevaluable.

Patient charts were reviewed in detail. Data noted were date ofcommencement of therapy, date of termination of therapy and any reasonfor termination other than response to treatment. Patient demographicswere also recorded, as were any other medical illnesses. Medicalillnesses were divided grossly into those that are associated with orexacerbate GERD and those that do not.

Patient charts were examined for evidence of response to therapy. Asthis was largely a referral population, and a retrospective review,quantification of symptomatology based on scores, office visits and EDvisits was difficult. Therefore, applicant examined charts for evidenceof an overall change in patient symptoms. In specific, any data to pointtowards improvement, decline or lack of change were examined andrecorded.

Results.

A total of 33 pediatric patients to date have been treated with theabove-described suspension at the University of Missouri—Columbia. Ofthe 33 patients, 9 were excluded from the study, all based uponinsufficient data about commencement, duration or outcome in treatmentwith PPI therapy. This left 24 patients with enough data to drawconclusions.

Of the 24 remaining patients, 18 were males and 6 females. Ages atimplementation of PPI therapy ranged from 2 weeks of age to 9 years old.Median age at start of therapy was 26.5 months [mean of 37 mo.] Earlyon, reflux was usually documented by endoscopy and confirmed by pHprobe. Eventually, pH probe was dropped and endoscopy was the solemethod for documenting reflux, usually at the time of another surgery(most often T-tubes or adenoidectomy). Seven patients had pH probeconfirmation of GERD, whereas 18 had endoscopic confirmation of refluxincluding all eight. who had pH probing done (See Graphs 1 and 2 below).Reflux was diagnosed on endoscopy most commonly by cobblestoning of thetracheal wall, with laryngeal and pharyngeal cobblestoning as findingsin a few patients. Six patients had neither pH nor endoscopicdocumentation of GERD, but were tried on PPI therapy based onsymptomatology alone.

Past medical history was identified in each chart. Ten patients hadreflux-associated diagnoses. These were most commonly cerebral palsy,prematurity and Pierre Robin sequence. Other diagnoses wereCharcot-Marie-Tooth disease, Velocardiofacial syndrome, Down syndromeand De George's syndrome. Non-reflux medical history was also identifiedand recorded separately (See Table 2 below). Patients were, in general,referral patients from local family practice clinics, pediatricians, orother pediatric health care professionals. Most patients were referredto ENT for upper airway problems, sinusitis, or recurrent/chronic otitismedia that had been refractory to medical therapy as reported by theprimary care physician. Symptoms and signs most commonly found in thesepatients were recorded and tallied. All signs and symptoms were brokendown into six major categories: (1) nasal; (2) otologic; (3)respiratory; (4) gastrointestinal; (5) sleep-related; and (6) other. Themost common problems fell into one or all of the first 3 categories (SeeTable 1 below).

Most patients had been treated in the past with medical therapy in theform of antibiotics, steroids, asthma medications and otherdiagnosis-appropriate therapies. In addition, nine of the patients hadbeen on reflux therapy in the past, most commonly in the form ofconservative therapy such as head of bed elevation 30°, avoidance ofevening snacks, avoidance of caffeinated beverages as well as cisaprideand ranitidine (See Graph 3 below).

The proton pump inhibitor suspension used in this group of patients wasChoco-Base suspension of either lansoprazole or omeprazole. The dosingwas very uniform, with patients receiving doses of either 10 or 20 mg ofomeprazole and 23 mg of lansoprazole. Initially, in April of 1996 whentherapy was first instituted 10 mg of omeprazole was used. There were 3patients in this early phase who were treated initially with 10 mg po qdof omeprazole. All three subsequently were increased to either 20 mg poqd of omeprazole or 23 mg po qd of lansoprazole. All remaining patientswere given either the 20 mg omeprazole or the 23 mg lansoprazoletreatment qd, except in one case, where 30 mg of lansoprazole was used.Patients were instructed to take their doses once per day, preferably atnight in most cases. Suspensions were all filled through the Universityof Missouri Pharmacy at Green Meadows. This allowed for tracking ofusage through refill-data.

Most patients responded favorably to and tolerated the once daily dosingof Choco-Base proton pump inhibitor suspension. Two patients haddocumented adverse effects associated with the use of the PPIsuspension. In one a patient, the mother reported increased burping upand dyspepsia, which was thought to be related to treatment failure. Theother patient had small amounts of bloody stools per mother. Thispatient never had his stool tested, as his bloody stool promptlyresolved upon cessation of therapy, with no further sequellae. The other23 patients had no documented adverse effects.

Patients were categorized based on review of clinic notes and chartreview into general categories: (1) improved; (2) unchanged; (3) failed;and (4) inconclusive. Of 24 patients with sufficient data for follow up,18 showed improvement in symptomatology upon commencement of PPI therapy[72%]. The seven who did not respond were analyzed and grouped. Threeshowed no change in symptomatology and clinical findings while ontherapy, one complained of worsening symptoms while on therapy, onepatient had therapy as prophylaxis for surgery, and two stopped therapyjust after its commencement (see graph 4). Setting aside the cases inwhich therapy was stopped before conclusions could be drawn and the casein which PPI therapy was for purely prophylactic reasons, leaves (17/21)81% of patients that responded to Choco-Base suspension. This means that19% (4/21) of patients received no apparent benefit from PPI therapy. Ofall these patients, only 4% complained of worsening symptoms and theside effects were 4% (1/21) and were mild bloody stool that completelyresolved upon cessation of therapy.

Discussion.

GERD in the pediatric population is relatively common, affecting almost50% of newborns. Even though most infants outgrow physiologic reflux,pathologic reflux still affects approximately 5% of all children,throughout childhood. Recently considerable data has pointed to refluxas an etiologic factor in extra-esophageal areas. GERD has beenattributed to sinusitis, dental caries, otitis media, asthma, apnea,arousal, pneumonia, bronchitis, and cough, among others. Despite thecommon nature of reflux, there seems to have been little improvement intherapy for reflux, especially in the non-surgical arena.

The standard of therapy for the treatment of GERD in the pediatricpopulation has become a progression from conservative therapy to acombination of a pro-kinetic agent and H-2 blocker therapy. Nonetheless,many patients fail this treatment protocol and become surgicalcandidates. In adults, PPI therapy is effective in 90% of those treatedfor gastroesophageal reflux disease. As a medical alternative to the H-2blockers, the proton pump inhibitors have not been studied extensivelyin the pediatric population. Part of the reason for this lack of datamay be related to the absence of a suitable dosage formulation for thisvery young population, primarily under 2 years of age, that does notswallow capsules or tablets. It would be desirable to have a true liquidformulation (solution or suspension) with good palatability such as isused for oral antibiotics, decongestants, antihistamines, H-2 blockers,cisapride, metoclopramide, etc. The use of lansoprazole granules(removed from the gelatin capule) and sprinkled on applesauce has beenapproved by the Food and Drug Administration as an alternative method ofdrug administration in adults but not in children. Published data arelacking on the efficacy of the lansoprazole sprinkle method in children.Omeprazole has been studied for bioequivalence as a sprinkle in adultsand appears to produce comparable serum concentrations when compared tothe standard capsule. Again no data are available on the omeprazolesprinkle in children. An additional disadvantage of omeprazole is itstaste which is quinine-like. Even when suspended in juice, applesauce orthe like, the bitter nature of the medicine is easily tasted even if onegranule is chewed. For this reason applicant eventually progressed touse lansoprazole in Choco-Base. Pantoprazole and rabeprazole areavailable as enteric-coated tablets only. Currently, none of the protonpump inhibitors available in the United States are approved forpediatric use. There is some controversy as to what the appropriatedosage should be in this group of patients. A recent review by IsraelD., et al. suggests that effective PPI dosages should be higher thanthat originally reported, i.e., from 0.7 mg/kg to 2 or 3 mg/kgomeprazole. Since toxicity with the PPI's is not seen even at >50 mg/kg,there appears little risk associated with the higher dosages. Based onobservations at the University of Missouri consistent with the findingsof this review, applicant established a simple fixed dosage regimen of10 ml Choco-Base suspension daily. This 10 ml dose provided 20 mgomeprazole and 23 mg lansoprazole.

In the ICU setting, the University of Missouri-Columbia has been usingan unflavored PPI suspension given once daily per various tubes(nasogastric, g-tube, jejunal feeding tube, duo tube, etc.) for stressulcer prophylaxis. It seemed only logical that if this therapy could bemade into a palatable form, it would have many ideal drugcharacteristics for the pediatric population. First, it would be liquid,and therefore could be administered at earlier ages. Second, if madeflavorful it could help to reduce noncompliance. Third, it could affordonce daily dosing, also helping in reducing noncompliance. In theprocess, applicant discovered that the dosing could be standardized,which nearly eliminated dosing complexity.

Choco-Base is a product which protects drugs which are acid labile, suchas proton pump inhibitors, from acid degradation. The first fewpediatric patients with reflux prescribed Choco-Base were sickerpatients. They had been on prior therapy and had been diagnosed both bypH probe and endoscopy. In the first few months, applicant treatedpatients with 10 mg of omeprazole qd (1 mg/kg) and found this to besomewhat ineffective, and quickly increased the dosing to 20 mg (2mg/kg) of omeprazole. About halfway through the study, applicant beganusing lansoprazole 23 mg po qd. Applicant's standard therapy was theneither 20 mg of omeprazole or 23 mg of lansoprazole once daily. Theextra 3 mg of lansoprazole is related only to the fact that the finalconcentration was 2.25 mg/ml, and applicant desired to keep dosingsimple, so he used a 10 ml suspension.

The patients that were treated represented a tertiary care centerpopulation, and they were inherently sicker and refractory to medicaltherapy in the past. The overall 72% success rate is slightly lower thanthe 90% success rates of PPIs in the adult population, but this can beattributed to the refractory nature of their illness, most having failedprior non-PPI treatment. The population in this study is not indicativeof general practice populations.

Conclusion.

PPI therapy is a beneficial therapeutic option in the treatment ofreflux related symptoms in the pediatric population. Its once dailydosing and standard dosing scheme combined with a palatable formulationmakes it an ideal pharmacologic agent.

TABLE 1 Symptoms Patient Numbers Nasal: 35 Sinusitis 7 Congestion 8Nasal discharge 16 Other 4 Otologic: 26 Otitis Media 17 Otorrhea 9Respiratory: 34 Cough 10 Wheeze 11 Respiratory Distress: 5 Pneumonia 2Other 6 Gastrointestinal: 10 Abdominal Pain 1 Reflux/Vomiting 4 Other 4Sleep Disturbances: 11 Other 2

TABLE 2 Past Medical History Number of Patients Reflux Associated: 12Premature 5 Pierre-Robin 2 Cerebral Palsy 2 Down Syndrome 1Charcot-Marie-Tooth 1 Velocardiofacial Syndrome 1 Other Medical History12 Cleft Palate 3 Asthma 3 Autism 2 Seizure Disorder 1 Diabetes Mellitus1 Subglottic Stenosis 1 Tracheostomy Dependent 1

FORMULATION 1 PART A INGREDIENTS AMOUNT (mg) Omeprazole 200 Sucrose26000 Sodium Bicarbonate 9400 Cocoa 1800 Corn Syrup Solids 6000 SodiumCaseinate 1000 Soy Lecithin 150 Sodium Chloride 35 Tricalcium Phosphate20 Dipotassium Phosphate 12 Silicon Dioxide 5 Sodium Stearoyl Lactylate5 PART B INGREDIENTS AMOUNT (ml) Distilled Water 100 COMPOUNDINGINSTRUCTIONS Add Part B to Part A to create a total volume ofapproximately 130 ml with an omeprazole concentration of about 1.5mg/ml. FORMULATION 2 PART A INGREDIENTS (mg) AMOUNT (mg) Sucrose 26000Cocoa 1800 Corn Syrup Solids 6000 Sodium Caseinate 1000 Soy Lecithin 150Sodium Chloride 35 Tricalcium Phosphate 20 Dipotassium Phosphate 12Silicon Dioxide 5 Sodium Stearoyl Lactylate 5 PART B INGREDIENTS AMOUNTDistilled Water  100 ml Sodium Bicarbonate 8400 mg Omeprazole  200 mgCOMPOUNDING INSTRUCTIONS Mix the constituents of Part B togetherthoroughly and then add to Part A. This results in a total volume ofapproximately 130 ml with an omeprazole concentration of about 1.5mg/ml. FORMULATION 3 PART A INGREDIENTS (mg) AMOUNT (mg) Sucrose 26000Sodium Bicarbonate 9400 Cocoa 1800 Corn Syrup Solids 6000 SodiumCaseinate 1000 Soy Lecithin 150 Sodium Chloride 35 Tricalcium Phosphate20 Dipotassium Phosphate 12 Silicon Dioxide 5 Sodium Stearoyl Lactylate5 PART B INGREDIENTS AMOUNT Distilled Water 100 ml Omeprazole 200 mgCOMPOUNDING INSTRUCTIONS This formulation is reconstituted at the timeof use by a pharmacist. Part B is mixed first and is then uniformlymixed with the components of Part A. A final volume of about 130 ml iscreated having an omeprazole concentration of about 1.5 mg/ml.FORMULATION 4 PART A INGREDIENTS (mg) AMOUNT (mg) Sucrose 26000 Cocoa1800 Corn Syrup Solids 6000 Sodium Caseinate 1000 Soy Lecithin 150Sodium Chloride 35 Tricalcium Phosphate 20 Dipotassium Phosphate 12Silicon Dioxide 5 Sodium Stearoyl Lactylate 5 PART B INGREDIENTS AMOUNTDistilled Water  100 ml Sodium Bicarbonate 8400 mg Omeprazole  200 mgCOMPOUNDING INSTRUCTIONS This formulation is reconstituted at the timeof use by a pharmacist. Part B is mixed first and is then uniformlymixed with the components of Part A. A final volume of about 130 ml iscreated having an omeprazole concentration of about 1.5 mg/ml.

In all four of the above formulations, lansoprazole or other PPI can besubstituted for omeprazole in equipotent amounts. For example, 300 mg oflansoprazole may be substituted for the 200 mg of omeprazole.Additionally, aspartame can be substituted for sucrose, and thefollowing other ingredients can be employed as carriers, adjuvants andexcipients: maltodextrin, vanilla, carragreenan, mono and diglycerides,and lactated monoglycerides. One skilled in the art will appreciate thatnot all of the ingredients are necessary to create a Choco-Baseformulation that is safe and effective.

Omeprazole powder or enteric coated granules can be used in eachformulation. If the enteric coated granules are used, the coating iseither dissolved by the aqueous diluent or inactivated by trituration inthe compounding process.

Applicant additionally analyzed the effects of a lansoprazole Choco-Baseformulation on gastric pH using a pH meter (Fisher Scientific) in oneadult patient versus lansoprazole alone. The patient was first given a30 mg oral capsule of Prevacid®, and the patient's gastric pH wasmeasured at 0, 4, 8, 12, and 16 hours post dose. The results areillustrated in FIG. 4.

The Choco-Base product was compounded according to Formulation 1 above,except 300 mg of lansoprazole was used instead of omeprazole. A dose of30 mg lansoprazole Choco-Base was orally administered at hour 18 postlansoprazole alone. Gastric pH was measured using a pH meter at hours18, 19, 24, 28, 32, 36, 40, 48, 52, and 56 post lansoprazole alone dose.

FIG. 4 illustrates the lansoprazole/cocoa combination resulted in higherpH_(s) at hours 19-56 than lansoprazole alone. at hours 4-18. Therefore,the combination of the lansoprazole with chocolate enhanced thepharmacologic activity of the lansoprazole. The results establish thatthe sodium bicarbonate as well as chocolate flavoring and calcium wereall able to stimulate the activation of the proton pumps, perhaps due tothe release of gastrin. Proton pump inhibitors work by functionallyinhibiting the proton pump and effectively block activated proton pumps(primarily those inserted into the secretory canalicular membrane) Byfurther administering the proton pump inhibitor with one of theseactivators or enhancers, there is a synchronization of activation of theproton pump with the absorption and subsequent parietal cellconcentrations of the proton pump inhibitor. As illustrated in FIG. 4,this combination produced a much longer pharmacologic effect than whenthe proton pump inhibitor was administered alone.

EXAMPLE VI

Combination Tablet Delivering Bolus and Time-released Doses of PPI

Tablets were compounded using known methods by forming an inner core of10 mg omeprazole powder mixed with 750 mg sodium bicarbonate, and anouter core of 10 mg omeprazole enteric-coated granules mixed with knownbinders and excipients. Upon ingestion of the whole tablet, the tabletdissolves and the inner core is dispersed in the stomach where it isabsorbed for immediate therapeutic effect. The enteric-coated granulesare later absorbed in the duodenum to provide symptomatic relief laterin the dosing cycle. This tablet is particularly useful in patients whoexperience breakthrough gastritis between conventional doses, such aswhile sleeping or in the early morning hours.

EXAMPLE VII

Therapeutic Application

Patients were evaluable if they met the following criteria: had two ormore risk factors for SRMD (mechanical ventilation, head injury, severeburn, sepsis, multiple, trauma, adult respiratory distress syndrome,major surgery, acute renal failure, multiple operative procedures,coagulotherapy, significant hyportension, acid-base disorder, andhepatic failure), gastric pH of ≦4 prior to study entry, and noconcomitant prophylaxis for SRMD.

The omeprazole solution was prepared by mixing 10 ml of 8.4% sodiumbicarbonate with the contents of a 20 mg capsule of omeprazole (Merck &Co.. Inc., West Point, Pa.) to yield. a solution having a finalomeprazole concentration of 2 mg/ml.

Nasogastric (ng) tubes were placed in the patients and an omeprazoledosage protocol of buffered 40 mg omeprazole solution (2 mg omeprazole/1ml NaHCO₃—8.4%) followed by 40 mg of the same buffered omeprazolesolution in eight hours, then 20 mg of the same buffered omeprazolesolution per day, for five days. After each buffered omeprazole solutionadministration, nasogastric suction was turned off for thirty minutes.

Eleven patients were evaluable. All patients were mechanicallyventilated. Two hours after the initial 40 mg dose of bufferedomeprazole solution, all patients had an increase in gastric pH togreater than eight as shown in FIG. 1. Ten of the eleven patientsmaintained a gastric pH of greater than or equal to four whenadministered 20 mg omeprazole solution. One patient required 40 mgomeprazole solution per day (closed head. injury, five total riskfactors for SRMD). Two patients were changed to omeprazole solutionafter having developed clinically significant upper gastrointestinalbleeding while receiving conventional intravenous H₂-antagonists.Bleeding subsided in both cases after twenty-four hours. Clinicallysignificant upper gastrointestinal bleeding did not occur in the othernine patients. Overall mortality was 27%, mortality attributable toupper gastrointestinal bleeding was 0%. Pneumonia developed in onepatient after initiating omeprazole therapy and was present upon theinitiation of omeprazole therapy in another patient. The mean length ofprophylaxis was five days.

A pharmacoeconomic analysis revealed a difference in the total cost ofcare for the prophylaxis of SRMD:

ranitidine (Zantac®) continuous infusion intravenously (150 mg/24hours)×five days $125.50;

cimetidine (Tagamet®) continuous infusion intravenously (900 mg/24hours)×five days $109.61;

sucralfate one gm slurry four times a day per (ng) tube×five days$73.00; and

buffered omeprazole solution regimen per (ng) tube×five days $65.70.

This example illustrates the efficacy of the buffered omeprazolesolution of the present invention based on the increase in gastric pH,safety and cost of the buffered omeprazole solution as a method for SRMDprophylaxis.

EXAMPLE VIII

Effect on pH

Experiments were carried out in order to determine the effect of theomeprazole solution (2 mg omeprazole/1 ml NaHCO₃—8.4%) administration onthe accuracy of subsequent pH measurements through a nasogastric tube.

After preparing a total of 40 mg of buffered omeprazole solution, in themanner of Example VII, doses were administered into the stomach,usually, through a nasogastric (ng) tube. Nasogastric tubes from ninedifferent institutions were gathered for an evaluation. Artificialgastric fluid (gf) was prepared according to the USP. pH recordings weremade in triplicate using a Microcomputer Portable pH meter model 6007(Jenco Electronics Ltd., Taipei, Taiwan).

First, the terminal portion (tp) of the nasogastric tubes was placedinto a glass beaker containing the gastric fluid. A 5 ml aliquot ofgastric fluid was aspirated through each tube and the pH recorded; thiswas called the “pre-omeprazole solution/suspension measurement.” Second,the terminal portion (tp) of each of the nasogastric tubes was removedfrom the beaker of gastric fluid and placed into an empty beaker. Twenty(20) mg of omeprazole solution was delivered through each of thenasogastric tubes and flushed with 10 ml of tap water. The terminalportion (tp) of each of the nasogastric tubes was placed back into thegastric fluid. After a one hour incubation, a 5 ml aliquot of gastricfluid was aspirated through each nasogastric tube and the pH recorded;this was called the “after first dose SOS [Simplified OmeprazoleSolution] measurement.” Third, after an additional hour had passed, thesecond step was repeated; this was called the “after second dose SOS[Simplified Omeprazole Solution] measurement.” In addition to thepre-omeprazole measurement, the pH of the gastric fluid was checked intriplicate after the second and third steps. A change in the pHmeasurements of +/− 0.3 units was considered significant. The Friedmantest was used to compare the results. The Friedman test is a two wayanalysis of variance which is used when more than two related samplesare of interest, as in repeated measurements.

The results of these experiments are outlined in Table 1.

TABLE 1 ng1 ng2 ng3 ng4 ng5 ng6 ng7 ng8 ng9 [1] gf 1.3 1.3 1.3 1.3 1.31.3 1.3 1.3 1.3 Pre SOS [2] gf p 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.31^(st) dose 1.3←check of fg pH [3] gf p 1.3 1 3 1.4 1.4 1.4 1.3 1.4 1.31.3 2^(nd) Dose 1.3←check of gf pH SOS pH = 9.0

Table 1 illustrates the results of the pH measurements that were takenduring the course of the experiment. These results illustrate that therewere no statistically significant latent effects of omeprazole solutionadministration (per nasogastric tube) on the accuracy of subsequent pHmeasurements obtained through the same nasogastric tube.

EXAMPLE IX

Efficacy of Buffered Omeprazole Solution in Ventilated Patients

Experiments were performed in order to determine the efficacy, safety,and cost of buffered omeprazole solution in mechanically ventilatedcritically ill patients who have at least one additional risk factor forstress-related mucosal damage.

Patients: Seventy-five adult, mechanically ventilated patients with atleast one additional risk factor for stress-related mucosal damage.

Interventions: Patients received 20 ml omeprazole solution (prepared asper Example VII and containing 40 mg of omeprazole) initially, followedby a second 20 ml dose six to eight hours later, then 10 ml (20 mg)daily. Omeprazole solution according to the present invention wasadministered through a nasogastric tube, followed by 5-10 ml of tapwater. The nasogastric tube was clamped for one to two hours after eachadministration.

Measurements and Main Results: The primary outcome measure wasclinically significant gastrointestinal bleeding determined byendoscopic evaluation, nasogastric aspirate examination, orheme-positive coffee ground material that did not clear with lavage andwas associated with a five percent decrease in hematocrit. Secondaryefficacy measures were gastric pH measured four hours after omeprazolewas first administered, mean gastric pH after omeprazole was started,and the lowest gastric pH during omeprazole therapy. Safety-relatedoutcomes included the incidence of adverse events and the incidence ofpneumonia. No patient experienced clinically significant uppergastrointestinal bleeding after receiving omeprazole suspension. Thefour-hour post omeprazole gastric pH was 7.1 (mean), the mean gastric pHafter starting omeprazole was 6.8 (mean) and the lowest pH afterstarting omeprazole was 5.6 (mean). The incidence of pneumonia wastwelve percent. No patient in this high-risk population experienced anadverse event or a drug interaction that was attributable to omeprazole.

Conclusions: Omeprazole solution prevented clinically significant upper,gastrointestinal bleeding and maintained gastric pH above 5.5 inmechanically ventilated critical care patients without producingtoxicity.

Materials and Methods

The study protocol was approved by the Institutional Review Board forthe University of Missouri at Columbia.

Study Population: All adult (>18 years old) patients admitted to thesurgical intensive care and burn unit at the University of MissouriHospital with an intact stomach, a nasogastric tube in place, and ananticipated intensive care unit stay of at least forty-eight hours wereconsidered for inclusion in the study. To be included patients also hadto have a gastric pH of <4, had to be mechanically ventilated and haveone of the following additional risk factors for a minimum oftwenty-four hours after initiation of omeprazole suspension: head injurywith altered level of consciousness, extensive burns (>20% Body SurfaceArea), acute renal failure, acid-base disorder, multiple trauma,coagulopathy, multiple operative procedures, coma, hypotension forlonger than one hour or sepsis (see Table 2). Sepsis was defined as thepresence of invasive. pathogenic organisms or their toxins in blood ortissues resulting in a systematic response that included two or more ofthe following: temperature greater than 38° C. or less than 36° C.,heart rate greater than 90 beats/minute, respiratory rate greater than20 breaths/minute (or _(p)O₂ less than 75 mm Hg), and white blood cellcount greater than 12,000 or less than 4,000 cells/mm³ or more than 10percent bands (Bone, Let's Agree on Terminology: Definitions of Sepsis,Crit. Care Med., 19: 27 (1991)). Patients in whom H₂-antagonist therapyhad failed or who experienced an adverse event while receivingH₂-antagonist therapy were also included.

Patients were excluded from the study if they were receiving azoleantifungal agents through the nasogastric tube; were likely to swallowblood (e.g., facial and/or sinus fractures, oral lacerations); hadsevere thrombocytopenia (platelet count less than 30,000 cells/mm³) ;were receiving enteral feedings through the nasogastric tube; or had ahistory of vagotomy, pyloroplasty, or gastroplasty. In addition,patients with a gastric pH above four for forty-eight hours after ICUadmission (without, prophylaxis) were not eligible for participation.Patients who developed bleeding within the digestive tract that was notstress-related mucosal damage (e.g., endoscopically verified varicealbleeding or Mallory-Weiss tears, oral lesions, nasal tears due toplacement of the nasogastric tube) were excluded from the efficacyevaluation and categorized as having non-stress-related mucosalbleeding. The reason for this exclusion is the confounding effect ofnon-stress-related mucosal bleeding on efficacy-related outcomes, suchas the use of nasogastric aspirate inspection to define clinicallysignificant upper gastrointestinal bleeding.

Study Drug Administration: Omeprazole solution was prepared immediatelybefore administration by the patient's nurse using the followinginstructions: empty the contents of one or two 20 mg omeprazolecapsule(s) into an empty 10 ml syringe (with 20 gauge needle in place)from which the plunger has been removed. (Omeprazole delayed-releasecapsules, Merck & Co., Inc., West Point, Pa.); replace the plunger anduncap the needle; withdraw 10 ml of 8.4% sodium bicarbonate solution or20 ml if 40 mg given (Abbott Laboratories, North Chicago, Ill.), tocreate a concentration of 2 mg omeprazole per ml of 8.4% sodiumbicarbonate; and allow the enteric coated pellets of omeprazole tocompletely breakdown, 30 minutes (agitation is helpful). The omeprazolein the resultant preparation is partially dissolved and partiallysuspended. The preparation should have a milky white appearance withfine sediment and should be shaken before administration. The solutionwas not administered with acidic substances. A high pressure liquidchromatography study was performed that demonstrated that thispreparation of simplified omeprazole suspension maintains >90% potencyfor seven days at room temperature. This preparation remained free ofbacterial and fungal contamination for thirty days when stored at roomtemperature (See Table 5).

The initial dose of omeprazole solution was 40 mg, followed by a second40 mg dose six to eight hours later, then a 20 mg daily doseadministered at 8:00 AM. Each dose was administered through thenasogastric tube. The nasogastric tube was then flushed with 5-10 ml oftap water and clamped for at least one hour. Omeprazole therapy wascontinued until there was no longer a need for stress ulcer prophylaxis(usually after the nasogastric tube was removed and the patient wastaking water/food by mouth, or after the patient was removed frommechanical ventilation).

Primary Outcome Measures: The primary outcome measure in this study wasthe rate of clinically significant stress-related mucosal bleedingdefined as endoscopic evidence of stress-related mucosal bleeding orbright red blood per nasogastric tube that did not clear after a5-minute lavage or persistent Gastroccult (SmithKline Diagnostics,Sunnyville, Calif.) positive coffee ground material for four consecutivehours that did not clear with lavage (at least 100 ml) and produced a 5%decrease in hematocrit.

Secondary Outcome Measures: The secondary efficacy measures were gastricpH measured four hours after omeprazole was administered, mean gastricpH after starting omeprazole and lowest gastric pH during omeprazoleadministration. Gastric pH was measured immediately after aspiratinggastric contents through the nasogastric tube. pH paper (pHydrionimproved pH papers, Microessential Laboratory, Brooklyn, N.Y.) was usedto measure gastric aspirate pH. The pH range of the test strips was 1 to11, in increments of one pH unit. Gastric pH was measured before theinitiation of omeprazole solution therapy, immediately before each dose,and every four hours between doses.

Other secondary outcome measures were incidence of adverse events(including drug interactions) and pneumonia. Any adverse event thatdeveloped during the study was recorded. Pneumonia was defined usingindicators adapted from the Centers for Disease Prevention and Controldefinition of nosocomial pneumonia (Garner et al., 1988). According tothese criteria, a patient who has pneumonia is one who has rales ordullness to percussion on physical examination of the chest or has achest radiograph that shows new or progressive infiltrate(s),consolidation, cavitation, or pleural effusion and has at least two ofthe following present: new purulent sputum or changes in character ofthe sputum, an organism isolated from blood culture, fever orleukocytosis, or evidence of infection from a protective specimen brushor bronchoalveolar lavage. Patients who met the criteria for pneumoniaand were receiving antimicrobial agents for the treatment of pneumoniawere included in the pneumonia incidence figure. These criteria werealso used as an initial screen before the first dose of study drug wasadministered to determine if pneumonia was present prior to the start ofomeprazole suspension.

Cost of Care Analysis: A pharmacoeconomic evaluation of stress ulcerprophylaxis using omeprazole solution was performed. The evaluationincluded total drug cost (acquisition and administration), actual costsassociated with adverse events (e.g., psychiatry consultation for mentalconfusion), costs associated with clinically significant uppergastrointestinal bleeding. Total drug cost was calculated by adding theaverage institutional costs of omeprazole 20 mg capsules, 50 ml sodiumbicarbonate vials, and 10 ml syringes with needle; nursing time (drugadministration, pH monitoring); pharmacy time (drug preparation); anddisposal costs. Costs associated with clinically significant uppergastrointestinal bleeding included endoscopy charges and accompanyingconsultation fees, procedures required to stop the bleeding (e.g.,surgery, hemostatic agents, endoscopic procedures), increased hospitallength of stay (as assessed by the attending physician), and cost ofdrugs used to treat the gastrointestinal bleeding.

Statistical Analysis: The paired t-test (two-tailed) was used to comparegastric pH before and after omeprazole solution administration and tocompare gastric pH before omeprazole solution administration with themean and lowest gastric pH value measured after beginning omeprazole.

Results:

Seventy-seven patients met the inclusion and exclusion criteria andreceived omeprazole solution (See FIG. 2). Two patients were excludedfrom the efficacy evaluation because the protocol for omeprazoleadministration was not followed. In one case, the omeprazoleenteric-coated pellets had not completely broken down prior to theadministration of the first two doses, which produced an erratic effecton gastric pH. The gastric pH increased to above six as soon as thepatient was given a dose of omeprazole solution (in which the entericcoated pellets of omeprazole had been allowed to completely breakdown).

The reason for the second exclusion was that nasogastric suctioning wasnot turned off after the omeprazole dose was administered. This resultedin a transient effect on gastric pH. The suction was turned off withsubsequent omeprazole doses, and control of gastric pH was achieved. Twopatients were considered efficacy failures because omeprazole failed tomaintain adequate gastric pH control on the standard omeprazole 20mg/day maintenance dose. When the omeprazole dose was increased to 40mg/day (40 mg once/day or 20 mg twice/day), gastric pH was maintainedabove four in both patients. These two patients were included in thesafety and efficacy evaluations, including the gastric pH analysis.After the two patients were declared failures, their pH values were nolonger followed.

The ages of the remaining seventy-five patients ranged from eighteen toeighty-seven years; forty-two patients were male and thirty-three werefemale. All patients were mechanically ventilated during the study.Table 2 shows the frequency of risk factors for stress-related bleedingthat were exhibited by the patients in this study. The most common riskfactors in this population were mechanical ventilation and majorsurgery. The range of risk factors for any given patient was two to ten,with a mean of 3 (±1) (standard deviation). Five patients enrolled inthe study had developed clinically significant bleeding while receivingcontinuous infusions of ranitidine (150 mg/24 hr) or cimetidine (900mg/24 hr). In all five cases, the bleeding subsided and the gastric pHrose to above five within thirty-six hours after initiating omeprazoletherapy. Three patients were enrolled after having developed twoconsecutive gastric pH values below three while receiving anH₂-antagonist (in the doses outlined above). In all three cases, gastricpH rose to above five within four hours after omeprazole therapy wasinitiated. Four other patients were enrolled in this study afterexperiencing confusion (n=2) or thrombocytopenia (n=2) duringH₂-antigens therapy. Within thirty-six hours of switching therapy, theseadverse events resolved.

Stress-related Mucosal Bleeding and Mortality: None of the sixty-fivepatients who received buffered omeprazole solution as their initialprophylaxis against stress-related mucosal bleeding developed overt orclinically significant upper gastrointestinal bleeding. In four of thefive patients who had developed upper gastrointestinal bleeding beforestudy entry, bleeding diminished to the presence of occult blood only(Gastroccult-positive) within eighteen hours of starting omeprazolesolution; bleeding stopped in all patients within thirty-six hours. Theoverall mortality rate in this group of critically ill patients waseleven percent. No death was attributable to upper gastrointestinalbleeding or the use of omeprazole solution.

Gastric pH: The mean (±standard deviation) pre-omeprazole gastric pH was3.5±1.9. Within four hours of omeprazole administration, the gastric pHrose to 7.1±1.1 (See FIG. 3); this difference was significant (p<0.001).The differences between pre-omeprazole gastric pH and the mean andlowest gastric pH measurements during omeprazole administration (6.8±0.6and 5.6±1.3, respectively) were also statistically significant(p<0.001).

Safety: Omeprazole solution was well tolerated in this group ofcritically ill patients. Only one patient with sepsis experienced anadverse event that may have been drug-related thrombocytopenia. However,the platelet count continued to fall after omeprazole was stopped. Theplatelet count then returned to normal despite reinstitution ofomeprazole therapy. Of note, one patient on a jet ventilatorcontinuously expelled all liquids placed in her stomach up and outthrough her mouth, and thus was unable to continue on omeprazole. No.clinically. significant drug interactions with omeprazole were notedduring the study period. As stated above, metabolic alkalosis is apotential concern in patients receiving sodium bicarbonate. However, theamount of sodium bicarbonate in omeprazole solution was small (12 mEq/10ml) and no electrolyte abnormalities were found.

Pneumonia: Pneumonia developed in nine (12%) patients receivingomeprazole solution. Pneumonia was present in an additional fivepatients before the start of omeprazole therapy.

Pharmacoeconomic evaluation: The average length of treatment was ninedays. The cost of care data are listed in Tables 3 and 4. The costs ofdrug acquisition, preparation, and delivery for some of the traditionalagents used in the prophylaxis of stress-related upper gastrointestinalbleeding are listed in Table 3. There were no costs to add from toxicityassociated with omeprazole solution. Since two of seventy-five patientsrequired 40 mg of omeprazole solution daily to adequately controlgastric pH, the acquisition/preparation cost should reflect this. Theadditional 20 mg of omeprazole with vehicle adds seven cents per day tothe cost of care. Therefore, the daily cost of care for omeprazolesolution in the prophylaxis of stress-related mucosal bleeding was$12.60 (See Table 4).

Omeprazole solution is a safe and effective therapy for the preventionof clinically significant stress-related mucosal bleeding in criticalcare patients. The contribution of many risk factors to stress-relatedmucosal damage has been challenged recently. All of the patients in thisstudy had at least one risk factor that has clearly been associated withstress-related mucosal damage—mechanical ventilation. Previous trialsand data from a recently published study show that stress ulcerprophylaxis is of proven benefit in patients at risk and, therefore, itwas thought to be unethical to include a placebo group in this study. Noclinically significant upper gastrointestinal bleeding occurred duringomeprazole solution therapy. Gastric pH was maintained above 4 onomeprazole 20 mg/day in seventy-three of seventy-five patients. Noadverse events or drug interaction associated with omeprazole wereencountered.

TABLE 2 Mech Major Multi- Head Hypo- Renal Multiple Acid/ Liver VentSurgery trauma Injury tension Failure Sepsis Operation Base Coma FailureBurn 75 61 35 16 14 14 14 12 10 4 2 2 Risk factors present in patientsin this study (n = 75)

TABLE 3 Per day RANITIDINE (day-9) Rantidine 150 mg/24 hr 6.15 AncillaryProduct (1) Piggyback (60%) 0.75 Ancillary Product (2) micro tubing(etc.) 2.00 Ancillary Product (3) filter .40 Sterile Prep required yesR.N. time ($24/hr) 20 minutes/day (includes pH 8.00 monitoring) R.Ph.time, hood maint. 3 minutes ($40/hr) 2.00 Pump cost $29/24 hrs × 50%)14.50 TOTAL far 9 days → 304.20 RANITIDINE Cost per day → 33.80CIMETIDINE (day 1-9) Cimetidine 900 mg/24 hr 3.96 Ancillary Product (1)Piggyback 1.25 Ancillary Product (2) micro tubing (etc.) 2.00 AncillaryProduct (3) filter .40 Sterile Prep required yes R.N. time ($24/hr) 20minutes/day (includes pH 8.00 R.Ph. time, hood maint. monitoring) Pumpcost 3 minutes ($40/hr) 2.00 TOTAL for 9 days $29/24 hrs × 50%) 14.50CIMETIDINE Cost per day → 288.99 SUCRALFATE (day 1-9) → 32.11 Sucralfate1 Gm × 4 2.40 Ancillary Product (1) syringe .20 Sterile Prep required noR.N. time ($24/hr) 30 minutes/day (includes pH 12.00 monitoring) TOTALfor 9 days → 131.40 SUCRALFATE Cost per day → 14.60 Note: Does notinclude the cost of failure and/or adverse effect. Acquisition,preparation and delivery costs of traditional agents.

EXAMPLE X

Bacteriostatic and Fungistatic Effects of Omeprazole Solution

The antimicrobial or bacteriostatic effects of the omeprazole solutionwere analyzed by applicant. An omeprazole solution (2 mg/ml of 8.4%sodium bicarbonate) made according to the present invention was storedat room temperature for four weeks and then was analyzed for fungal andbacterial growth. Following four weeks of storage at room temperature,no bacterial or fungal growth was detected.

An omeprazole solution (2 mg/ml of 8.4% sodium bicarbonate) made inaccordance with the present invention was stored at room temperature fortwelve weeks and then was analyzed for fungal and bacterial growth.After twelve weeks of incubation at room temperature, no fungal orbacterial growth was detected.

The results of these experiments illustrate the bacteriostatic andfungistatic characteristics of the omeprazole solution of the presentinvention.

EXAMPLE XI

Bioequivalency Study

Healthy male and female study participants over the age of 18 will berandomized to receive omeprazole in the following forms:

(a) 20 mg of a liquid formulation of approximately 20 mg. omeprazole in4.8.mEq sodium bicarbonate qs to 10 ml with water;

(b) 20 mg of a liquid formulation of approximately 2 mg omeprazole per 1ml of 8.4% sodium bicarbonate.

(c) Prilosec® (omeprazole) 20 mg capsule;

(d) Capsule prepared by inserting the contents of an omeprazole 20 mgcapsule into a #4 empty gelatin capsule (Lilly) uniformly dispersed in240 mg of sodium bicarbonate powder USP to form an inner capsule. Theinner capsule is then inserted into a #00 empty gelatin capsule (Lilly)together with a homogeneous mixture of 600 mg sodium bicarbonate USPand110 mg pregelatinized starch NF.

Methodology

After appropriate screening and consent, healthy volunteers will berandomized to receive one of the following four regimens as randomlyassigned by Latin Square. Each subject will be crossed to each regimenaccording to the randomization sequence until all subjects have receivedall four regimens (with one week separating each regimen).

Regimen A (20 mg omeprazole in 4.8 mEq sodium bicarbonate in 10 mlvolume); Regimen B (20 mg omeprazole in 10 ml 8.4% sodium bicarbonate in10 ml volume); Regimen C (an intact 20 mg omeprazole capsule); Regimen D(Capsule in capsule formulation, see above). For each dose/week,subjects will have an i.v. saline lock placed for blood sampling. Foreach regimen, blood samples will be taken over 24 hours a total of 16times (with the last two specimens obtained 12 hours and 24 hours afterdrug administration).

Patient Eligibility

Four healthy females and four healthy males will be consented for thestudy.

Inclusion Criteria

Signed informed consent.

Exclusion Criteria

1. Currently taking H₂-receptor antagonist, antacid, or sucralfate.

2. Recent (within 7 days) therapy with lansoprazole, omeprazole, orother proton pump inhibitor.

3. Recent (within 7 days) therapy with warfarin.

4. History of variceal bleeding.

5. History of peptic ulcer disease or currently active G.I. bleed.

6. History of vagotomy or pyloroplasty.

7. Patient has received an investigational drug within 30 days.

8. Treatment with ketoconazole or itraconazole.

9. Patient has an allergy to omeprazole.

Pharmocokinetic Evaluation and Statistical Analysis

Blood samples will be centrifuged within 2 hours of collection and theplasma will then separated and frozen at −10° C. (or lower) untilassayed. Pharmacokinetic variables will include: time to peakconcentration, mean peak concentration, AUC (0-t) and (0-infinity).Analysis of variance will be used to detect statistical difference.Bioavailability will be assessed by the 90% confidence interval of thetwo one-sided tests on the natural logarithm of AUC.

HPLC Analysis

Omeprazole and internal standard (H168/24) will be used. Omeprazole andinternal standard will be measured by modification of the proceduredescribed by Amantea and Narang. (Amantea Mass., Narang PK. ImprovedProcedure for Quantification of Omeprazole and Metabolites UsingReversed-Phased High Performance Liquid Chromotography. J.Chromatography 426; 216-222. 1988). Briefly, 20 ul of omeprazole 2 mg/mlNaHCO₃ or Choco-Base omeprazole suspension and 190 ul of the internalstandard are vortexed with 150 ul of carbonate buffer (pH=9.8), 5 ml ofdichloroethane, 5 ml of hexane, and 980 ul of sterile water. After thesample is centrifuged, the organic layer is extracted and dried over anitrogen stream. Each pellet is reconstituted with 150 ul of mobilephase (40% methanol, 52% 0.025 phosphate buffer, 8% acetonitrile,pH=7.4). Of the reconstituted sample, 75 ul is injected onto a C₁₈ 5 Ucolumn equilibrated with the same mobile phase at 1.1 ml/min. Underthese conditions, omeprazole is eluted at approximately 5 minutes, andthe internal standard at approximately 7.5 minutes. The standard curveis linear over the concentration range 0-3 mg/ml (in previous work withSOS), and the between-day coefficient of variation has been <8% at allconcentrations. The typical mean R2 for the standard curve has been 0.98in prior work with SOS (omeprazole 2 mg/ml NaHCO₃ 8.4%).

Applicant expects that the above experiments will demonstrate there ismore rapid absorption of formulations (a), (b) and (d) as compared tothe enteric coated granules of formulation (c). Additionally, applicantexpects that although there will be a difference in the rates ofabsorption among forms (a) through (d), the extent of absorption (asmeasured by the area under the curve (AUC)) should be similar among theformulations (a) through (d).

EXAMPLE XII

Intraveneous PPI in Combination With Oral Parietal Cell Activator

Sixteen (16) normal, healthy male and female study subjects over the ageof 18 will be randomized to receive pantoprazole as follows:

(a) 40 mg IV over 15 to 30 minutes in combination with a 20 ml oral doseof sodium bicarbonate 8.4%; and

(b) 40 mg IV over 15 to 30 minutes in combination with a 20 ml oral doseof water.

The subjects will receive a single dose of (a) or (b) above, and will becrossed-over to (a) and (b) in random fashion. Serum concentrations ofpantoprazole versus time after administration data will be collected, aswell as. gastric pH control as measured with an indwelling pH probe.

Further, similar studies are contemplated wherein chocolate or otherparietal cell activator is substituted for the parietal cell activatorsodium bicarbonate, and other PPIs are substituted for pantoprazole. Theparietal cell activator can be administered either within about 5minutes before, during or within about 5 minutes after the IV dose ofPPI.

Applicant expects that these studies will demonstrate that significantlyless IV PPI is required to achieve therapeutic effect when it is givenin combination with an oral parietal cell activator.

Additionally, administration kits of IV PPI and oral parietal cellactivator can be packaged in many various forms for ease ofadministration and to optimize packing and shipping the product. Suchkits can be in unit dose or multiple dose form.

EXAMPLE XIII

Twelve (12) Month Stability of Omeprazole Solution

A solution was prepared by mixing 8.4% sodium bicarbonate withomeprazole to produce a final concentration of 2 mg/ml to determine thestability of omeprazole solution after 12 months. The resultantpreparation was stored in clear glass at room temperature, refrigeratedand frozen. Samples were drawn after thorough agitation from the storedpreparations at the prescribed times. The samples were then stored at70° C. Frozen samples remained frozen until they were analyzed. When thecollection process was completed, the samples were shipped to alaboratory overnight on dry ice for analysis. Samples were agitated for30 seconds and sample aliquots were analyzed by HPLC in triplicateaccording to well known methods. Omeprazole and the internal standardwere measured by a modification of the procedure described by Amanteaand Narang. Amantea Mass., Narang PK, Improved Procedure ForQuantitation Of Omeprazole And Metabolites Using Reverse-PhasedHigh-Performance Liquid Chromatography, J. Chromatography, 426: 216-222(1988). Twenty (20) ul of the omeprazole 2 mg/ml NaHCO₃ solution and 100ul of the internal standard solution were vortexed with 150 ul ofcarbonate buffer (pH=9.8), 5 ml dichloroethane, 5 ml hexane, and 980 ulof sterile water. The sample was centrifuged and the organic layer wasextracted and dried over a nitrogen stream. Each pellet wasreconstituted with 150 ul of mobile phase (40% methanol, 52% 0.025phosphate buffer, 8% acetonitrile, pH=7.4). Of the reconstituted sample,75 ul were injected onto a C185u column equilibrated with the samemobile phase at 1.1 ml/min. Omeprazole was eluted at ˜5 min, and theinternal standard at ˜7.5 min. The standard curve was linear over theconcentrated range 0-3 mg/ml, and between-day coefficient of variationwas <8% at all concentrations. Mean R2 for the standard curve was 0.980.

The 12 month sample showed stability at greater than 90% of the originalconcentration of 2 mg/ml. (i.e., 1.88 mg/ml, 1.94 mg/ml, 1.92 mg/ml).

Throughout this application various publications and patents arereferenced by citation and number. The disclosure of these publicationsand patents in their entireties are hereby incorporated by referenceinto this application in order to more fully describe the state of theart to which this invention pertains.

The invention has been described in an illustrative manner, and it is tobe understood the terminology used is intended to be in the nature ofdescription rather than of limitation. Obviously, many modifications,equivalents, and variations of the present invention are possible inlight of the above teachings. Therefore, it is to be understood thatwithin the scope of the appended claims, the invention may be practicedother than as specifically described.

I claim:
 1. A solid pharmaceutical composition in a dosage form that isnot enteric-coated, comprising: active ingredients consistingessentially of: (a) a non-enteric coated proton pump inhibitor selectedfrom the group consisting of omeprazole, lansoprazole, rabeprazole,esomeprazole, pantoprazole, pariprazole, and leminoprazole, or anenantiomer, isomer, free base, or salt thereof, in an amount ofapproximately 5 mg to approximately 300 mg; and (b) at least onebuffering agent selected from the group consisting of sodiumbicarbonate, potassium bicarbonate, a calcium salt, and a magnesiumsalt, in an amount of approximately 0.1 mEq to approximately 2.5 mEq permg of proton pump inhibitor; wherein the dosage form is selected fromthe group consisting of suspension tablet, chewable tablet, effervescentpowder, and effervescent tablet.
 2. The composition as recited in claim1, wherein the proton pump inhibitor is omeprazole.
 3. The compositionas recited in claim 1, wherein the proton pump inhibitor islansoprazole.
 4. The composition as recited in claim 1, wherein theproton pump inhibitor is rabeprazole.
 5. The composition as recited inclaim 1, wherein the proton pump inhibitor is esomeprazole.
 6. Thecomposition as recited in claim 1, wherein the proton pump inhibitor ispantoprazole.
 7. The composition as recited in claim 1, wherein theproton pump inhibitor is pariprazole.
 8. The composition as recited inclaim 1, wherein the proton pump inhibitor is leminoprazole.
 9. Thecomposition as recited in claim 1, further comprising at least oneflavoring agent.
 10. The composition as recited in claim 1, furthercomprising an anti-foaming agent.
 11. The composition as recited inclaim 1, wherein the dosage form is a suspension tablet.
 12. Thecomposition as recited in claim 1, wherein the dosage form is a chewabletablet.
 13. The composition as recited in claim 12, further comprisingaspartame.
 14. The composition as recited in claim 1, wherein the dosageform is an effervescent powder.
 15. The composition as recited in claim1, wherein the dosage form is an effervescent tablet.
 16. Thecomposition as recited in claim 1, wherein the buffering agent is atleast about 1680 mg sodium bicarbonate.
 17. The composition as recitedin claim 1, wherein the buffering agent is about 1000 mg to about 1680mg sodium bicarbonate.
 18. A method of producing a liquid pharmaceuticalcomposition, comprising: combining the composition recited in claim 11with an aqueous medium.
 19. A method of producing a liquidpharmaceutical composition, comprising: combining the compositionrecited in claim 12 with an aqueous medium.
 20. A method of producing aliquid pharmaceutical composition, comprising: combining the compositionrecited in claim 14 with an aqueous medium.
 21. A method of producing aliquid pharmaceutical composition, comprising: combining the compositionrecited in claim 15 with an aqueous medium.
 22. A method for treating anacid-caused gastrointestinal disorder in a subject in need thereof,comprising: administering to the subject the dosage form of claim 1 viaa route selected from the group consisting of oral, nasogastric, andgastric tube.
 23. The method as recited in claim 22, wherein thedisorder is selected from the group consisting of duodenal ulcerdisease, gastric ulcer disease, gastroesophageal reflux disease, erosiveesophagitis, poorly responsive symptomatic gastroesophageal refluxdisease, pathological gastrointestinal hypersecretory disease, ZollingerEllison Syndrome, and acid dyspepsia.
 24. A method for treating anacid-caused gastrointestinal disorder in a subject in need thereof,comprising: administering to the subject a solid pharmaceuticalcomposition in a dosage form that is not enteric-coated; wherein thecomposition comprises active ingredients consisting essentially of: (a)a therapeutically effective amount of approximately 5 mg toapproximately 300 mg of a non-enteric coated proton pump inhibitorselected from the group consisting of omeprazole, lansoprazole,rabeprazole, esomeprazole, pantoprazole, pariprazole, and leminoprazole,or an enantiomer, isomer, derivative, free base, or salt thereof; and(b) a buffering agent in an amount of approximately 1.0 mEq toapproximately 150 mEq selected from the group consisting of abicarbonate salt of a group IA metal, a calcium salt, and a magnesiumsalt, wherein the buffering agent is in an amount sufficient to elevategastric acid pH of the subject's stomach to prevent or inhibit gastricacid degradation of the non-enteric coated proton pump inhibitor andachieve sufficient bioavailability of the proton pump inhibitor in thesubject to elicit a therapeutic effect.
 25. The method of claim 24,wherein the calcium salt is selected from the group consisting ofcalcium acetate, calcium glycerophosphate, calcium chloride, calciumhydroxide, calcium lactate, calcium bicarbonate, calcium gluconate, andother calcium salts.
 26. The method of claim 24, wherein the sodiumbicarbonate is in an amount from about 1000 mg to about 1680 mg.
 27. Themethod of claim 24, wherein the sodium bicarbonate is in an amount of atleast about 1680 mg.
 28. The method of claim 24, wherein the calciumsalt is calcium carbonate present in an amount from about 250 mg toabout 1000 mg.
 29. The method of claim 24, wherein the calcium salt iscalcium carbonate present in an amount from about 500 mg to about 1000mg.
 30. The method of claim 24, wherein the calcium salt is calciumcarbonate present in an amount of at least about 1000 mg.
 31. The methodof claim 24, wherein the buffering agent is in an amount of at least 10mEq.
 32. The method of claim 24, wherein the buffering agent is in anamount from about 10 mEq to about 70 mEq.
 33. The method of claim 24,wherein the buffering agent is in an amount from about 20 mEq to about40 mEq.
 34. The method of claim 24, wherein the proton pump inhibitor isin an amount from about 10 mg to about 100 mg.
 35. The method of claim24, wherein the proton pump inhibitor is omeprazole.
 36. The method ofclaim 35, wherein the omeprazole is present in an amount of about 10 mg.37. The method of claim 35, wherein the omeprazole is present in anamount of about 20 mg.
 38. The method of claim 35, wherein theomeprazole is present in an amount of about 40 mg.
 39. The method ofclaim 35, wherein the omeprazole is present in an amount of about 60 mg.40. The method of claim 35, wherein the omeprazole is present in anamount of about 80 mg.
 41. The method of claim 35, wherein theomeprazole is present in an amount of about 100 mg.
 42. The method ofclaim 24, wherein the proton pump inhibitor is lansoprazole.
 43. Themethod of claim 42, wherein the lansoprazole is present in an amount ofabout 15 mg.
 44. The method of claim 42, wherein the lansoprazole ispresent in an amount of about 30 mg.
 45. The method of claim 42, whereinthe lansoprazole is present in an amount of about 45 mg.
 46. The methodof claim 42, wherein the lansoprazole is present in an amount of about60 mg.
 47. The method of claim 42, wherein the lansoprazole is presentin an amount of about 90 mg.
 48. The method of claim 42, wherein thelansoprazole is present in an amount of about 100 mg.
 49. The method ofclaim 24, wherein the proton pump inhibitor is micronized.
 50. Themethod of claim 24, wherein the composition is in a dosage form selectedfrom the group consisting of a tablet, powder, suspension tablet,chewable tablet, capsule, effervescent powder, effervescent tablet,pellets, and granules.
 51. The method of claim 24, wherein the subjectis a human.
 52. The method of claim 24, wherein the dosage form furthercomprises a flavoring agent.
 53. The method of claim 52, wherein theflavoring agent comprises aspartame, chocolate, root beer, peppermint,spearmint, or watermelon, and combinations of any of the foregoing. 54.The method of claim 24, wherein the composition is provided as aseparate component of a kit.
 55. The method of claim 24, wherein thedisorder is selected from the group consisting of duodenal ulcerdisease, gastric ulcer disease, gastroesophageal reflux disease, erosiveesophagitis, poorly responsive symptomatic gastroesophageal refluxdisease, pathological gastrointestinal hypersecretory disease, ZollingerEllison Syndrome, and acid dyspepsia.
 56. The method of claim 24,wherein the dosage form is administered once or twice a day.
 57. A solidpharmaceutical composition in a dosage form that is not enteric-coated,comprising: active ingredients consisting essentially of: (a) atherapeutically effective amount of a non-enteric coated proton pumpinhibitor selected from the group consisting of omeprazole,lansoprazole, rabeprazole, esomeprazole, pantoprazole, pariprazole, andleminoprazole, or an enantiomer, isomer, derivative, free base, or saltthereof; and (b) a buffering agent selected from the group consisting ofsodium bicarbonate, and calcium carbonate, in an amount more than about40 times the amount of the proton pump inhibitor on a weight to weightbasis in the composition.
 58. The composition as recited in claim 57,wherein the buffering agent is sodium bicarbonate.
 59. The compositionas recited in claim 57, wherein the sodium bicarbonate is in an amountfrom about 400 mg to about 4000 mg.
 60. The composition as recited inclaim 57, wherein the sodium bicarbonate is in an amount of at leastabout 800 mg.
 61. The composition as recited in claim 57, wherein thebuffering agent is calcium carbonate.
 62. The composition as recited inclaim 57, wherein the calcium carbonate is in an amount from about 400mg to about 4000 mg.
 63. The composition as recited in claim 61, whereinthe calcium carbonate is in an amount from about 500 mg to about 1000mg.
 64. The composition as recited in claim 61, wherein the calciumcarbonate is in an amount of at least about 800 mg.
 65. The compositionas recited in claim 57, wherein the proton pump inhibitor is in anamount from about 10 mg to about 100 mg.
 66. The composition as recitedin claim 57, wherein the proton pump inhibitor is omeprazole.
 67. Thecomposition as recited in claim 66, wherein the omeprazole is present inan amount of about 10 mg.
 68. The composition as recited in claim 66,wherein the omeprazole is present in an amount of about 20 mg.
 69. Thecomposition as recited in claim 66, wherein the omeprazole is present inan amount of about 40 mg.
 70. The composition as recited in claim 66,wherein the omeprazole is present in an amount of about 60 mg.
 71. Thecomposition as recited in claim 66, wherein the omeprazole is present inan amount of about 80 mg.
 72. The composition as recited in claim 66,wherein the omeprazole is present in an amount of about 100 mg.
 73. Thecomposition as recited in claim 57, wherein the proton pump inhibitor islansoprazole.
 74. The composition as recited in claim 73, wherein thelansoprazole is present in an amount of about 15 mg.
 75. The compositionas recited in claim 73, wherein the lansoprazole is present in an amountof about 30 mg.
 76. The composition as recited in claim 73, wherein thelansoprazole is present in an amount of about 45 mg.
 77. The compositionas recited in claim 73, wherein the lansoprazole is present in an amountof about 60 mg.
 78. The composition as recited in claim 73, wherein thelansoprazole is present in an amount of about 90 mg.
 79. The compositionas recited in claim 73, wherein the lansoprazole is present in an amountof about 100 mg.
 80. The composition as recited in claim 57, wherein theproton pump inhibitor is micronized.
 81. The composition as recited inclaim 57, wherein the composition is in a dosage form selected from thegroup consisting of a tablet, powder, suspension tablet, chewabletablet, capsule, effervescent powder, effervescent tablet, pellets, andgranules.
 82. The composition as recited in claim 57, further comprisinga flavoring agent comprising aspartame, chocolate, root beer,peppermint, spearmint, or watermelon, and combinations of any of theforegoing.
 83. The composition as recited in claim 57, wherein theamount of the buffering agent is more than about 50 times the amount ofthe proton pump inhibitor on a weight to weight basis in thecomposition.
 84. The composition as recited in claim 57, wherein theamount of the buffering agent is more than about 60 times the amount ofthe proton pump inhibitor on a weight to weight basis in thecomposition.
 85. The composition as recited in claim 57, wherein theamount of the buffering agent is more than about 70 times the amount ofthe proton pump inhibitor on a weight to weight basis in thecomposition.
 86. The composition as recited in claim 57, wherein theamount of the buffering agent is more than about 80 times the amount ofthe proton pump inhibitor on a weight to weight basis in thecomposition.
 87. The composition as recited in claim 57, wherein theamount of the buffering agent is more than about 90 times the amount ofthe proton pump inhibitor on a weight to weight basis in thecomposition.
 88. The composition as recited in claim 57, wherein theamount of the buffering agent is more than about 100 times the amount ofthe proton pump inhibitor on a weight to weight basis in thecomposition.
 89. The composition as recited in claim 57, wherein thecomposition is provided as a separate component of a kit.
 90. A methodof producing a liquid pharmaceutical composition comprising: combiningthe dosage form of claim 57 with an aqueous medium.
 91. A method fortreating an acid-caused gastrointestinal disorder in a subject in needthereof, comprising: administering to the subject the dosage form asrecited in claim 57 via a route selected from the group consisting oforal, nasogastric, and gastric tube.
 92. The method as recited in claim91, wherein the disorder is selected from the group consisting ofduodenal ulcer disease, gastric ulcer disease, gastroesophageal refluxdisease, erosive esophagitis, poorly responsive symptomaticgastroesophageal reflux disease, pathological gastrointestinalhypersecretory disease, Zollinger Ellison Syndrome, and acid dyspepsia.93. The method as recited in claim 91, wherein the composition isadministered once or twice a day.
 94. A method for administering aliquid pharmaceutical composition to a subject, comprising: combiningthe pharmaceutical composition as recited in claim 57 with an aqueousmedium to form a suspension, and orally administering the suspension tothe subject in a single dose without administering an additionalbuffering agent.
 95. The composition as recited in claim 1, wherein theproton pump inhibitor is in an amount from about 10 mg to about 100 mg.96. The composition as recited in claim 95, wherein the proton pumpinhibitor is omeprazole.
 97. The composition as recited in claim 95,wherein the omeprazole is present in an amount of about 10 mg.
 98. Thecomposition as recited in claim 95, wherein the omeprazole is present inan amount of about 20 mg.
 99. The composition as recited in claim 95,wherein the omeprazole is present in an amount of about 40 mg.
 100. Thecomposition as recited in claim 95, wherein the omeprazole is present inan amount of about 60 mg.
 101. The composition as recited in claim 95,wherein the omeprazole is present in an amount of about 80 mg.
 102. Thecomposition as recited in claim 95, wherein the omeprazole is present inan amount of about 100 mg.
 103. The composition as recited in claim 95,wherein the proton pump inhibitor is lansoprazole.
 104. The compositionas recited in claim 103, wherein the lansoprazole is present in anamount of about 15 mg.
 105. The composition as recited in claim 103,wherein the lansoprazole is present in an amount of about 30 mg. 106.The composition as recited in claim 103, wherein the lansoprazole ispresent in an amount of about 45 mg.
 107. The composition as recited inclaim 103, wherein the lansoprazole is present in an amount of about 60mg.
 108. The composition as recited in claim 103, wherein thelansoprazole is present in an amount of about 90 mg.
 109. Thecomposition as recited in claim 103, wherein the lansoprazole is presentin an amount of about 100 mg.
 110. The composition as recited in claim1, wherein the proton pump inhibitor is micronized.
 111. The compositionas recited in claim 9, wherein the flavoring agent comprises aspartame,chocolate, root beer, peppermint, spearmint, or watermelon, andcombinations of any of the foregoing.
 112. The composition as recited inclaim 1, wherein the composition is provided as a separate component ofa kit.
 113. The composition of claim 1, wherein the buffering agentcomprises a bicarbonate salt of a Group IA metal. 114.The composition ofclaim 1, wherein the buffering agent comprises at least one of magnesiumhydroxide, magnesium lactate, magnesium gluconate, magnesium oxide,magnesium carbonate, or magnesium silicate.
 115. The composition ofclaim 1, wherein the buffering agent comprises at least one of calciumacetate, calcium glycerophosphate, calcium chloride, calcium hydroxide,calcium lactate, calcium carbonate, calcium bicarbonate, calciumgluconate, or other calcium salts.
 116. The composition of claim 1,further comprising a disintegrant, flow aid, lubricant, adjuvantexcipient, colorant, diluent, moistening agent, preservative, andpharmaceutically compatible carrier.
 117. The method of claim 24,wherein the composition further comprises a disintegrant, flow aid,lubricant, adjuvant, excipient, colorant, diluent, moistening agent,preservative, and pharmaceutically compatible carrier.
 118. Thecomposition of claim 57, further comprising a disintegrant, flow aid,lubricant, adjuvant, excipient, colorant, diluent, moistening agent,preservative, and pharmaceutically compatible carrier.